Quinazoles useful as modulators of ion channels

ABSTRACT

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels and calcium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

PRIORITY INFORMATION

This application is a divisional of U.S. patent application Ser. No. 10/792,688, filed Mar. 3, 2004, entitled “Quinazolines Useful as Modulators of Ion Channels”, now U.S. Pat. No. 7,678,802, which claims priority under 35U.S.C. §119 to U.S. Provisional Application Nos. 60/451,458 filed Mar. 3, 2003, entitled “Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels”, and 60/463,797, filed Apr. 18, 2003, entitled “Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels”, and the entire contents of each of these applications is hereby incorporated by reference.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors of ion channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

BACKGROUND OF THE INVENTION

Na channels are central to the generation of action potentials in all excitable cells such as neurons and myocytes. They play key roles in excitable tissue including brain, smooth muscles of the gastrointestinal tract, skeletal muscle, the peripheral nervous system, spinal cord and airway. As such they play key roles in a variety of disease states such as epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91)), pain (See, Waxman, S. G., S. Dib-Hajj, et al. (1999) “Sodium channels and pain” Proc Natl Acad Sci USA 96(14): 7635-9 and Waxman, S. G., T. R. Cummins, et al. (2000) “Voltage-gated sodium channels and the molecular pathogenesis of pain: a review” J Rehabil Res Dev 37(5): 517-28), myotonia (See, Meola, G. and V. Sansone (2000) “Therapy in myotonic disorders and in muscle channelopathies” Neurol Sci 21(5): S953-61 and Mankodi, A. and C. A. Thornton (2002) “Myotonic syndromes” Curr Opin Neurol 15(5): 545-52), ataxia (See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations of voltage-gated sodium channels in movement disorders and epilepsy” Novartis Found Symp 241: 72-81), multiple sclerosis (See, Black, J. A., S. Dib-Hajj, et al. (2000) “Sensory neuron-specific sodium channel SNS is abnormally expressed in the brains of mice with experimental allergic encephalomyelitis and humans with multiple sclerosis” Proc Natl Acad Sci USA 97(21): 11598-602, and Renganathan, M., M. Gelderblom, et al. (2003) “Expression of Na(v)1.8 sodium channels perturbs the firing patterns of cerebellar purkinje cells” Brain Res 959(2): 235-42), irritable bowel (See, Su, X., R. E. Wachtel, et al. (1999) “Capsaicin sensitivity and voltage-gated sodium currents in colon sensory neurons from rat dorsal root ganglia” Am J Physiol 277(6 Pt 1): G1180-8, and Laird, J. M., V. Souslova, et al. (2002) “Deficits in visceral pain and referred hyperalgesia in Nav1.8 (SNS/PN3)-null mice” J Neurosci 22(19): 8352-6), urinary incontinence and visceral pain (See, Yoshimura, N., S. Seki, et al. (2001) “The involvement of the tetrodotoxin-resistant sodium channel Na(v)1.8 (PN3/SNS) in a rat model of visceral pain” J Neurosci 21(21): 8690-6), as well as an array of psychiatry dysfunctions such as anxiety and depression (See, Hurley, S. C. (2002) “Lamotrigine update and its use in mood disorders” Ann Pharmacother 36(5): 860-73).

Voltage gated Na channels comprise a gene family consisting of 9 different subtypes (NaV1.1-NaV1.9). As shown in Table 1, these subtypes show tissue specific localization and functional differences (See, Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94). Three members of the gene family (NaV1.8, 1.9, 1.5) are resistant to block by the well-known Na channel blocker TTX, demonstrating subtype specificity within this gene family. Mutational analysis has identified glutamate 387 as a critical residue for TTX binding (See, Noda, M., H. Suzuki, et al. (1989) “A single point mutation confers tetrodotoxin and saxitoxin insensitivity on the sodium channel II” FEBS Lett 259(1): 213-6).

TABLE 1 (Abbreviations: CNS = central nervous system, PNS = peripheral nervous sytem, DRG = dorsal root ganglion, TG = Trigeminal ganglion): Na isoform Tissue TTX IC50 Indications NaV1.1 CNS, PNS 10 nM Pain, Epilepsy, soma of neurodegeneration neurons NaV1.2 CNS, high in 10 nM Neurodegeneration axons Epilepsy NaV1.3 CNS, 15 nM Pain embryonic, injured nerves NaV1.4 Skeletal 25 nM Myotonia muscle NaV1.5 Heart 2 μM Arrythmia, long QT NaV1.6 CNS 6 nM Pain, movement disorders widespread, most abuntant NaV1.7 PNS, DRG, 25 nM Pain, Neuroendocrine terminals disorders neuroendocrine NaV1.8 PNS, small >50 μM Pain neurons in DRG & TG NaV1.9 PNS, small 1 μM Pain neurons in DRG & TG

In general, voltage-gated sodium channels (NaVs) are responsible for initiating the rapid upstroke of action potentials in excitable tissue in nervous system, which transmit the electrical signals that compose and encode normal and aberrant pain sensations. Antagonists of NaV channels can attenuate these pain signals and are useful for treating a variety of pain conditions, including but not limited to acute, chronic, inflammatory, and neuropathic pain. Known NaV antagonists, such as TTX, lidocaine (See Mao, J. and L. L. Chen (2000) “Systemic lidocaine for neuropathic pain relief” Pain 87(1): 7-17.) bupivacaine, phenyloin (See, Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8), lamotrigine (See, Rozen, T. D. (2001) “Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia” Headache 41 Suppl 1: S25-32 and Jensen, T. S. (2002) “Anticonvulsants in neuropathic pain: rationale and clinical evidence” Eur J Pain 6 (Suppl A): 61-8.), and carbamazepine (See, Backonja, M. M. (2002) “Use of anticonvulsants for treatment of neuropathic pain” Neurology 59(5 Suppl 2): S14-7), have been shown to be useful attenuating pain in humans and animal models.

Hyperalgesia (extreme sensitivity to something painful) that develops in the presence of tissue injury or inflammation reflects, at least in part, an increase in the excitability of high-threshold primary afferent neurons innervating the site of injury. Voltage sensitive sodium channels activation is critical for the generation and propagation of neuronal action potentials. There is a growing body of evidence indicating that modulation of NaV currents is an endogenous mechanism used to control neuronal excitability (See, Goldin, A. L. (2001) “Resurgence of sodium channel research” Annu Rev Physiol 63: 871-94.). Several kinetically and pharmacologically distinct voltage-gated sodium channels are found in dorsal root ganglion (DRG) neurons. The TTX-resistant current is insensitive to micromolar concentrations of tetrodotoxin, and displays slow activation and inactivation kinetics and a more depolarized activation threshold when compared to other voltage-gated sodium channels. TTX-resistant sodium currents are primarily restricted to a subpopulation of sensory neurons likely to be involved in nociception. Specifically, TTX-resistant sodium currents are expressed almost exclusively in neurons that have a small cell-body diameter; and give rise to small-diameter slow-conducting axons and that are responsive to capsaicin. A large body of experimental evidence demonstrates that TTX-resistant sodium channels are expressed on C-fibers and are important in the transmission of nociceptive information to the spinal cord.

Intrathecal administration of antisense oligo-deoxynucleotides targeting a unique region of the TTX-resistant sodium channel (NaV1.8) resulted in a significant reduction in PGE₂-induced hyperalgesia (See, Khasar, S. G., M. S. Gold, et al. (1998) “A tetrodotoxin-resistant sodium current mediates inflammatory pain in the rat” Neurosci Lett 256(1): 17-20). More recently, a knockout mouse line was generated by Wood and colleagues, which lacks functional NaV1.8. The mutation has an analgesic effect in tests assessing the animal's response to the inflammatory agent carrageenan (See, Akopian, A. N., V. Souslova, et al. (1999) “The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways” Nat Neurosci 2(6): 541-8.). In addition, deficit in both mechano- and thermoreception were observed in these animals. The analgesia shown by the Nav1.8 knockout mutants is consistent with observations about the role of TTX-resistant currents in nociception.

Immunohistochemical, in-situ hybridization and in-vitro electrophysiology experiments have all shown that the sodium channel NaV1.8 is selectively localized to the small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See, Akopian, A. N., L. Sivilotti, et al. (1996) “A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons” Nature 379(6562): 257-62.). The primary role of these neurons is the detection and transmission of nociceptive stimuli. Antisense and immunohistochemical evidence also supports a role for NaV1.8 in neuropathic pain (See, Lai, J., M. S. Gold, et al. (2002) “Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8” Pain 95(1-2): 143-52, and Lai, J., J. C. Hunter, et al. (2000) “Blockade of neuropathic pain by antisense targeting of tetrodotoxin-resistant sodium channels in sensory neurons” Methods Enzymol 314: 201-13.). NaV1.8 protein is upregulated along uninjured C-fibers adjacent to the nerve injury. Antisense treatment prevents the redistribution of NaV1.8 along the nerve and reverses neuropathic pain. Taken together the gene-knockout and antisense data support a role for NaV1.8 in the detection and transmission of inflammatory and neuropathic pain.

In neuropathic pain states there is a remodeling of Na channel distribution and subtype. In the injured nerve, expression of NaV1.8 and NaV1.9 are greatly reduced whereas expression of the TTX sensitive subunit NaV1.3 is 5-10 fold upregulated (See, Dib-Hajj, S. D., J. Fjell, et al. (1999) “Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain.” Pain 83(3): 591-600.) The timecourse of the increase in NaV1.3 parallels the appearance of allodynia in animal models subsequent to nerve injury. The biophysics of the NaV1.3 channel is distinctive in that it shows very fast repriming after inactivation following an action potential. This allows for sustained rates of high firing as is often seen in the injured nerve (See, Cummins, T. R., F. Aglieco, et al. (2001) “Nav1.3 sodium channels: rapid repriming and slow closed-state inactivation display quantitative differences after expression in a mammalian cell line and in spinal sensory neurons” J Neurosci 21(16): 5952-1.). NaV1.3 is expressed in the central and peripheral systems of man. NaV1.9 is similar to NaV1.8 as it is selectively localized to small sensory neurons of the dorsal root ganglion and trigeminal ganglion (See, Fang, X., L. Djouhri, et al. (2002). “The presence and role of the tetrodotoxin-resistant sodium channel Na(v)1.9 (NaN) in nociceptive primary afferent neurons.” J Neurosci 22(17): 7425-33.). It has a slow rate of inactivation and left-shifted voltage dependence for activation (See, Dib-Hajj, S., J. A. Black, et al. (2002) “NaN/Nav1.9: a sodium channel with unique properties” Trends Neurosci 25(5): 253-9.). These two biophysical properties allow NaV1.9 to play a role in establishing the resting membrane potential of nociceptive neurons. The resting membrane potential of NaV1.9 expressing cells is in the −55 to −50 mV range compared to −65 mV for most other peripheral and central neurons. This persistent depolarization is in large part due to the sustained low-level activation of NaV1.9 channels. This depolarization allows the neurons to more easily reach the threshold for firing action potentials in response to nociceptive stimuli. Compounds that block the NaV1.9 channel may play an important role in establishing the set point for detection of painful stimuli. In chronic pain states, nerve and nerve ending can become swollen and hypersensitive exhibiting high frequency action potential firing with mild or even no stimulation. These pathologic nerve swellings are termed neuromas and the primary Na channels expressed in them are NaV1.8 and NaV1.7 (See, Kretschmer, T., L. T. Happel, et al. (2002) “Accumulation of PN1 and PN3 sodium channels in painful human neuroma-evidence from immunocytochemistry” Acta Neurochir (Wien) 144(8): 803-10; discussion 810.). NaV1.6 and NaV1.7 are also expressed in dorsal root ganglion neurons and contribute to the small TTX sensitive component seen in these cells. NaV1.7 in particular my therefore be a potential pain target in addition to it's role in neuroendocrine excitability (See, Klugbauer, N., L. Lacinova, et al. (1995) “Structure and functional expression of a new member of the tetrodotoxin-sensitive voltage-activated sodium channel family from human neuroendocrine cells” Embo J 14(6): 1084-90).

NaV1.1 (See, Sugawara, T., E. Mazaki-Miyazaki, et al. (2001) “Nav1.1 mutations cause febrile seizures associated with afebrile partial seizures.” Neurology 57(4): 703-5.) and NaV1.2 (See, Sugawara, T., Y. Tsurubuchi, et al. (2001) “A missense mutation of the Na+ channel alpha II subunit gene Na(v)1.2 in a patient with febrile and afebrile seizures causes channel dysfunction” Proc Natl Acad Sci USA 98(11): 6384-9) have been linked to epilepsy conditions including febrile seizures. There are over 9 genetic mutations in NaV 1.1 associated with febrile seizures (See, Meisler, M. H., J. A. Kearney, et al. (2002) “Mutations of voltage-gated sodium channels in movement disorders and epilepsy” Novartis Found Symp 241: 72-81)

Antagonists for NaV1.5 have been developed and used to treat cardiac arrhythmias. A gene defect in NaV1.5 that produces a larger noninactivating component to the current has been linked to long QT in man and the orally available local anesthetic mexilitine has been used to treat this condition (See, Wang, D. W., K. Yazawa, et al. (1997) “Pharmacological targeting of long QT mutant sodium channels.” J Clin Invest 99(7): 1714-20).

Several Na channel blockers are currently used or being tested in the clinic to treat epilepsy (See, Moulard, B. and D. Bertrand (2002) “Epilepsy and sodium channel blockers” Expert Opin. Ther. Patents 12(1): 85-91.); acute (See, Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain” Cochrane Database Syst Rev 3), chronic (See, Wiffen, P., S. Collins, et al. (2000) “Anticonvulsant drugs for acute and chronic pain” Cochrane Database Syst Rev 3, and Guay, D. R. (2001) “Adjunctive agents in the management of chronic pain” Pharmacotherapy 21(9): 1070-81), inflammatory (See, Gold, M. S. (1999) “Tetrodotoxin-resistant Na+ currents and inflammatory hyperalgesia.” Proc Natl Acad Sci USA 96(14): 7645-9), and neuropathic pain (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain” Novartis Found Symp 241: 189-201, and Sandner-Kiesling, A., G. Rumpold Seitlinger, et al. (2002) “Lamotrigine monotherapy for control of neuralgia after nerve section” Acta Anaesthesiol Scand 46(10): 1261-4); cardiac arrhythmias (See An, R. H., R. Bangalore, et al. (1996) “Lidocaine block of LQT-3 mutant human Na+ channels” Circ Res 79(1): 103-8, and Wang, D. W., K. Yazawa, et al. (1997) “Pharmacological targeting of long QT mutant sodium channels” J Clin Invest 99(7): 1714-20); neuroprotection (See, Taylor, C. P. and L. S. Narasimhan (1997) “Sodium channels and therapy of central nervous system diseases” Adv Pharmacol 39: 47-98) and as anesthetics (See, Strichartz, G. R., Z. Zhou, et al. (2002) “Therapeutic concentrations of local anaesthetics unveil the potential role of sodium channels in neuropathic pain.” Novartis Found Symp 241: 189-201)

Calcium channels are membrane-spanning, multi-subunit proteins that allow Ca entry from the external milieu and concurrent depolarization of the cell's membrane potential. Traditionally calcium channels have been classified based on their functional characteristics such as low voltage or high voltage activated and their kinetics (L, T, N, P, Q). The ability to clone and express the calcium channel subunits has lead to an increased understanding of the channel composition that produces these functional responses. There are three primary subunit types that make up calcium channels—α1, α2δ, and β. The α1 is the subunit containing the channel pore and voltage sensor, α2 is primarily extracellular and is disulfide linked to the transmembrane δ subunit, β is nonglycosylated subunit found bound to the cytoplasmic region of the α1 subunit of the Ca channel. Currently the various calcium channel subtypes are believed to made up of the following specific subunits:

L-type, comprising subunits α_(1C)α_(1D)α_(1F), or α_(1S), α2δ and β_(3a)

N-Type, comprising subunits α_(1B), α2δ, β_(1b)

P-Type, comprising subunits α_(1A), α2δ, β_(4a)

Q-Type, comprising subunits α_(1A) (splice variant) α2δ, β_(4a)

R-Type, comprising subunits α_(1E), α2δ, β_(1b)

T-Type, comprising subunits α_(1G), α_(1H), or α_(1I)

Calcium channels play a central role in neurotransmitter release. Ca influx into the presynaptic terminal of a nerve process binds to and produces a cascade of protein-protein interactions (syntaxin 1A, SNAP-25 and synaptotagmin) that ultimately ends with the fusion of a synaptic vesical and release of the neurotransmitter packet. Blockade of the presynaptic calcium channels reduces the influx of Ca and produces a cubic X³ decrease in neurotransmitter release.

The N type Ca channel (CaV2.2) is highly expressed at the presynaptic nerve terminals of the dorsal root ganglion as it forms a synapse with the dorsal horn neurons in lamina I and II. These neurons in turn have large numbers of N type Ca channels at their presynaptic terminals as they synapse onto second and third order neurons. This pathway is very important in relaying pain information to the brain.

Pain can be roughly divided into three different types: acute, inflammatory, and neuropathic. Acute pain serves an important protective function in keeping the organism safe from stimuli that may produce tissue damage. Severe thermal, mechanical, or chemical inputs have the potential to cause severe damage to the organism if unheeded. Acute pain serves to quickly remove the individual from the damaging environment. Acute pain by its very nature generally is short lasting and intense. Inflammatory pain on the other had may last for much longer periods of time and it's intensity is more graded. Inflammation may occur for many reasons including tissue damage, autoimmune response, and pathogen invasion. Inflammatory pain is mediated by an “inflammatory soup” that consists of substance P, histamines, acid, prostaglandin, bradykinin, CGRP, cytokines, ATP, and neurotransmitter release. The third class of pain is neuropathic and involves nerve damage that results in reorganization of neuronal proteins and circuits yielding a pathologic “sensitized” state that can produce chronic pain lasting for years. This type of pain provides no adaptive benefit and is particularly difficult to treat with existing therapies.

Pain, particularly neuropathic and intractable pain is a large unmet medical need. Millions of individuals suffer from severe pain that is not well controlled by current therapeutics. The current drugs used to treat pain include NSAIDS, COX2 inhibitors, opioids, tricyclic antidepressants, and anticonvulsants. Neuropathic pain has been particularly difficult to treat as it does not respond well to opiods until high doses are reached. Gabapentin is currently the favored therapeutic for the treatment of neuropathic pain although it works in only 60% of patients where it shows modest efficacy. The drug is however very safe and side effects are generally tolerable although sedation is an issue at higher doses.

The N type Ca channel has been validated in man by intrathecal infusion of the toxin Ziconotide for the treatment of intractable pain, cancer pain, opioid resistant pain, and neuropathic and severe pain. The toxin has an 85% success rate for the treatment of pain in humans with a greater potency than morphine. An orally available N type Ca channel antagonist would garner a much larger share of the pain market. Ziconotide causes mast cell degranulation and produces dose-dependent central side effects. These include dizziness, nystagmus, agitation, and dysmetria. There is also orthostatic hypotension in some patients at high doses. The primary risk for this target involves the CNS side effects seen with Ziconotide at high dosing. These include dizziness, nystagmus, agitation, and dysmetria. There is also orthostatic hypotension in some patients at high doses. It is believed that this may be due to Ziconotide induced mast cell degranulation and/or its effects on the sympathetic ganglion that like the dorsal root ganglion also expresses the N type Ca channel. Use-dependent compounds that block preferentially in the higher frequency range >10 Hz should be helpful in minimizing these potential side-effect issues. The firing rate in man of the sympathetic efferents is in the 0.3 Hz range. CNS neurons can fire at high frequencies but generally only do so in short bursts of action potentials. Even with the selectivity imparted by use-dependence intrinsic selectivity against the L type calcium channel is still necessary as it is involved in cardiac and vascular smooth muscle contraction.

Unfortunately, as described above, the efficacy of currently used sodium channel blockers and calcium channel blockers for the disease states described above has been to a large extent limited by a number of side effects. These side effects include various CNS disturbances such as blurred vision, dizziness, nausea, and sedation as well more potentially life threatening cardiac arrhythmias and cardiac failure. Accordingly, there remains a need to develop additional Na channel and Ca channel antagonists, preferably those with higher potency and fewer side effects.

SUMMARY OF THE INVENTION

It has now been found that compounds of this invention, and pharmaceutically acceptable compositions thereof, are useful as inhibitors of voltage-gated sodium channels and calcium channels. These compounds have the general formula I:

or a pharmaceutically acceptable derivative thereof, wherein R¹, X, R³, x, and ring A are as defined below.

These compounds and pharmaceutically acceptable compositions are useful for treating or lessening the severity of a variety of diseases, disorders, or conditions, including, but not limited to, acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain.

DETAILED DESCRIPTION OF THE INVENTION

I. General Description of Compounds of the Invention

The present invention relates to compounds of formula I useful as inhibitors of voltage-gated sodium channels and calcium channels:

or a pharmaceutically acceptable salt thereof, wherein:

X is O or NR²;

wherein R¹ and R² are each independently an optionally substituted group selected from hydrogen, C₁₋₆aliphatic, or Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein R¹ and R², or the ring formed by R¹ and R² taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;

Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered monocyclic or bicyclic saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R⁵, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R^(5a), wherein q is 0-2;

x is 0-4;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X) is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R^(5a) is independently an optionally substituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments for compounds described directly above:

i) when x is 1 and R³ is optionally substituted 6-phenyl or 6-pyridyl, and R¹ is hydrogen, then R² is not Cy¹; and

ii) piperazine,1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4(2-furanylcarbonyl)-monohydrochloride and piperazine,1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-[(2,3-dihydro-1,4-benzodioxin-2-yl)carbonyl]- are excluded.

2. Compounds and Definitions:

Compounds of this invention include those described generally above, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th) Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry”, 5^(th) Ed., Ed.: Smith, M. B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally be substituted with one or more substituents, such as are illustrated generally above, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase “optionally substituted” is used interchangeably with the phrase “substituted or unsubstituted.” In general, the term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of hydrogen radicals in a given structure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40° C. or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term “aliphatic” or “aliphatic group”, as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as “carbocycle” “cycloaliphatic” or “cycloalkyl”), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, “cycloaliphatic” (or “carbocycle” or “cycloalkyl”) refers to a monocyclic C₃-C₈ hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule wherein any individual ring in said bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term “heteroaliphatic”, as used herein, means aliphatic groups wherein one or two carbon atoms are independently replaced by one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon. Heteroaliphatic groups may be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” groups.

The term “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” as used herein means non-aromatic, monocyclic, bicyclic, or tricyclic ring systems in which one or more ring members are an independently selected heteroatom. In some embodiments, the “heterocycle”, “heterocyclyl”, “heterocycloaliphatic”, or “heterocyclic” group has three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as in N-substituted pyrrolidinyl)).

The term “unsaturated”, as used herein, means that a moiety has one or more units of unsaturation.

The term “alkoxy”, or “thioalkyl”, as used herein, refers to an alkyl group, as previously defined, attached to the principal carbon chain through an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl”, “haloalkenyl” and “haloalkoxy” means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in “aralkyl”, “aralkoxy”, or “aryloxyalkyl”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” may be used interchangeably with the term “aryl ring”. The term “aryl” also refers to heteroaryl ring systems as defined hereinbelow.

The term “heteroaryl”, used alone or as part of a larger moiety as in “heteroaralkyl” or “heteroarylalkoxy”, refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and wherein each ring in the system contains 3 to 7 ring members. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents and thus may be “optionally substituted”. Unless otherwise defined above and herein, suitable substituents on the unsaturated carbon atom of an aryl or heteroaryl group are generally selected from halogen; —R^(o); —OR^(o); —SR^(o); phenyl (Ph) optionally substituted with R^(o); —O(Ph) optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substituted with R^(o); —CH═CH(Ph), optionally substituted with R^(o); —NO₂; —CN; —N(R^(o))₂; —NR^(o)C(O)R^(o); —NR^(o)C(S)R^(o); —NR^(o)C(O)N(R^(o))₂; —NR^(o)C(S)N(R^(o))₂; —NR^(o)CO₂R^(o); —NR^(o)NR^(o)C(O)R^(o); —NR^(o)NR^(o)C(O)N(R^(o))₂; —NR^(o)NR^(o)CO₂R^(o); —C(O)C(O)R^(o); —C(O)CH₂C(O)R^(o); —CO₂R^(o); —C(O)R^(o); —C(S)R^(o); —C(O)N(R^(o))₂; —C(S)N(R^(o))₂; —OC(O)N(R^(o))₂; —OC(O)R^(o); —C(O)N(OR^(o))R^(o); —C(NOR^(o))R^(o); —S(O)₂R^(o); —S(O)₃R^(o); —SO₂N(R^(o))₂; —S(O)R^(o); —NR^(o)SO₂N(R^(o))₂; —NR^(o)SO₂R^(o); —N(OR^(o))R^(o); —C(═NH)—N(R^(o))₂; —P(O)₂R^(o); —PO(R^(o))₂; —OPO(R^(o))₂; —(CH₂)₀₋₂NHC(O)R^(o); phenyl (Ph) optionally substituted with R^(o); —O(Ph) optionally substituted with R^(o); —(CH₂)₁₋₂(Ph), optionally substituted with R^(o); or —CH═CH(Ph), optionally substituted with R^(o); wherein each independent occurrence of R^(o) is selected from hydrogen, optionally substituted C₁₋₆ aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, —O(Ph), or —CH₂(Ph), or, notwithstanding the definition above, two independent occurrences of R^(o), on the same substituent or different substituents, taken together with the atom(s) to which each R^(o) group is bound, to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Optional substituents on the aliphatic group of R^(o) are selected from NH₂, NH(C₁₋₄aliphatic), N(C₁₋₄aliphatic)₂, halogen, C₁₋₄aliphatic, OH, O(C₁₋₄aliphatic), NO₂, CN, CO₂H, CO₂(C₁₋₄aliphatic), O(haloC₁₋₄ aliphatic), or haloC₁₋₄aliphatic, wherein each of the foregoing C₁₋₄aliphatic groups of R^(o) is unsubstituted.

An aliphatic or heteroaliphatic group, or a non-aromatic heterocyclic ring may contain one or more substituents and thus may be “optionally substituted”. Unless otherwise defined above and herein, suitable substituents on the saturated carbon of an aliphatic or heteroaliphatic group, or of a non-aromatic heterocyclic ring are selected from those listed above for the unsaturated carbon of an aryl or heteroaryl group and additionally include the following: ═O, ═S, ═NNHR*, ═NN(R*)₂, ═NNHC(O)R*, ═NNHCO₂(alkyl), ═NNHSO₂(alkyl), or ═NR*, where each R* is independently selected from hydrogen or an optionally substituted C₁₋₆ aliphatic group.

Unless otherwise defined above and herein, optional substituents on the nitrogen of a non-aromatic heterocyclic ring are generally selected from —R⁺, —N(R⁺)₂, —C(O)R⁺, —CO₂R⁺, —C(O)C(O)R⁺, —C(O)CH₂C(O)R⁺, —SO₂R⁺, —SO₂N(R⁺)₂, —C(═S)N(R⁺¹)₂, —C(═NH)—N(R⁺)₂, or —NR⁺SO₂R⁺; wherein R⁺ is hydrogen, an optionally substituted C₁₋₆ aliphatic, optionally substituted phenyl, optionally substituted —O(Ph), optionally substituted —CH₂(Ph), optionally substituted —(CH₂)₁₋₂(Ph); optionally substituted —CH═CH(Ph); or an unsubstituted 5-6 membered heteroaryl or heterocyclic ring having one to four heteroatoms independently selected from oxygen, nitrogen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R⁺, on the same substituent or different substituents, taken together with the atom(s) to which each R⁺ group is bound, form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Optional substituents on the aliphatic group or the phenyl ring of R⁺ are selected from —NH₂, —NH(C₁₋₄ aliphatic), —N(C₁₋₄ aliphatic)₂, halogen, C₁₋₄ aliphatic, —OH, —O(C₁₋₄ aliphatic), —NO₂, —CN, —CO₂H, CO₂(C₁₋₄ aliphatic), —O(halo C₁₋₄ aliphatic), or halo(C₁₋₄ aliphatic), wherein each of the foregoing C₁₋₄aliphatic groups of R⁺ is unsubstituted.

The term “alkylidene chain” refers to a straight or branched carbon chain that may be fully saturated or have one or more units of unsaturation and has two points of attachment to the rest of the molecule.

As detailed above, in some embodiments, two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined, herein), are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

Exemplary rings that are formed when two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined herein), are taken together with the atom(s) to which each variable is bound include, but are not limited to the following: a) two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined herein) that are bound to the same atom and are taken together with that atom to form a ring, for example, N(R^(o))₂, where both occurrences of R^(o) are taken together with the nitrogen atom to form a piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl group; and b) two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined herein) that are bound to different atoms and are taken together with both of those atoms to form a ring, for example where a phenyl group is substituted with two occurrences of OR^(o)

these two occurrences of R^(o) are taken together with the oxygen atoms to which they are bound to form a fused 6-membered oxygen containing ring:

It will be appreciated that a variety of other rings can be formed when two independent occurrences of R^(o) (or R⁺, R, R′ or any other variable similarly defined herein) are taken together with the atom(s) to which each variable is bound and that the examples detailed above are not intended to be limiting.

Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays.

3. Description of Exemplary Compounds:

As described generally above, for compounds of the invention, X is O or NR². Accordingly, in certain embodiments, X is NR², and compounds have the structure of formula I-A:

In other embodiments, X is O, and compounds have the structure of formula I-B:

In certain embodiments for compounds of general formula I-A, one of R¹ or R² is hydrogen, and the other of R¹ and R² is selected from an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—, or is Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In still other embodiments, R¹ and R² are each independently selected from Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or from an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In other embodiments, for compounds of formula I-A, one of R¹ or R² is hydrogen, and the other of R¹ or R² is an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—. In still other embodiments, the optionally substituted C₁₋₄aliphatic group is substituted with Cy¹, wherein Cy¹ is 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12 membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is optionally substituted with 0-5 independent occurrences of —R⁵. In yet other embodiments, one of R¹ or R² is hydrogen or C₁-C₄alkyl, and the other of R¹ or R² is —CH₂—Cy¹.

In yet other embodiments, for compounds of formula I-B, R¹ is an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—, —OCO, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In still other embodiments, for compounds of formula I-A, neither R¹ nor R² is hydrogen, and R¹ and R² are each independently selected from Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated, or partially unsaturated monocyclic or bicyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or from an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—, —OCO—, —NRCO—, —CONR—, SO₂NR—, or —NRSO_(2.—) In other embodiments, both R¹ and R² are an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO_(2—).

In some embodiments, for compounds of formula I, I-A or I-B, Cy¹ is selected from:

wherein R⁴ is previously defined and z is 0-4. Other exemplary rings include those shown below in Table 2.

In yet other embodiments, for compounds of formula I, I-A, and I-B, exemplary R¹ and R² groups are optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂(CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl. Other exemplary R¹ and R² groups include those shown below in Table 2.

In still other embodiments, for compounds of formula I-A, R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12 membered heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen, sulfur, or oxygen. In certain preferred embodiments, R¹ and R² are taken together with the nitrogen atom to which they are bound and form a group selected from:

wherein the ring formed by R¹ and R² taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, and z is 0-5.

In other embodiments, for compounds of formula I-A, R¹ and R² taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R¹ and R² taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin 1-yl (dd). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc).

In certain embodiments, z is 0-2. In other embodiments, z is 0 and the ring is unsubstituted. Preferred R⁴ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl. Other exemplary R⁴ groups are Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl. Still other exemplary R⁴ groups include those shown below in Table 2.

In certain embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In still other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRCOOR′. In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

As described generally above, for compounds of formulas I, I-A, or I-B, the quinazoline ring can be substituted with up to four independent occurrences of R³. In certain embodiments, x is 0-2. In other embodiments, x is 1 or 2. In still other embodiments x is 1 and R³ is substituted at the 6- or 7-position of the quinazoline ring. When the quinazoline ring is substituted (x is 1-4), R³ groups are halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl. In still other embodiments, each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy. In still other embodiments, x is 1 or 2 and each R³ group is independently halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′. In yet other embodiments, x is 1 or 2, and each R³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. IN yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. Other exemplary R³ groups include those shown below in Table 2.

As described generally above, for compounds of formula I, I-A, or I-B, Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R⁵, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R^(5a), wherein q is 0-2.

In certain embodiments, ring A is selected from:

In certain other embodiments, ring A is selected from optionally substituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yl.

In some embodiments, y is 0-5, q is 0-2, and R⁵ and R^(5a) groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected from C₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy.

In still other embodiments, y is 0, and q is 1 and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the other occurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

In still other embodiments, ring A is phenyl, y is 0, and q is 1 and R^(5a) is F substituted at the 2-position of the phenyl ring. In yet other embodiments, ring A is phenyl, y is 0, q is 1, and R^(5a) is OR′ substituted at the 2-position of the phenyl ring. In still other embodiments, ring A is phenyl, y is 0, q is 1 and R^(5a) is OH substituted at the 2-position of the phenyl ring. In yet other embodiments, ring A is phenyl, y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the other occurrence of R^(5a) is F, wherein OR′ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, ring A is phenyl, y is 0, q is 2 and one occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.

Other exemplary R⁵ and R^(5a) groups include those shown below in Table 2.

For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or NaV1.7.

Certain additional embodiments of compounds described generally above are described in more detail below. For example:

I. Compounds of Formula IA:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated, partially unsaturated, or fully unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein the ring formed by R¹ and R² taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;

Ring A is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein ring A is optionally substituted with y independent occurrences of —R⁵, wherein y is 0-5, and is additionally optionally substituted with q independent occurrences of R^(5a), wherein q is 0-2;

x is 0-4;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X) is independently selected from —R′, halogen, ═O, ═NR′, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R^(5a) is independently an optionally substituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionally substituted C₁₋₆aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, for compounds described directly above:

a. when R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 4-membered monocyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then 2-Oxazolidinone, 3-[(3R,4R)-2-oxo-1-(2-phenyl-4-quinazolinyl)-4-[2-(3-pyridinyl)ethenyl]-3-azetidinyl]-4-phenyl-, (4S)— is excluded;

b. when R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 5-membered monocyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then:

-   -   i. ring A is not optionally substituted         hexahydro-1H-1,4-diazepin-1-yl; and     -   ii. Benzenesulfonamide,         2-methoxy-5-[2-[[1-(2-phenyl-4-quinazolinyl)-3-pyrrolidinyl]amino]ethyl]-,         (R)—, bis(trifluoroacetate), and Benzenesulfonamide,         2-methoxy-5-[2-[[1-(2-phenyl-4-quinazolinyl)-3-pyrrolidinyl]amino]ethyl]-,         (S)—, bis(trifluoroacetate) are excluded;     -   iii. 3-Pyrrolidinamine, 1-(2-phenyl-4-quinazolinyl)-, and         (R)-3-Pyrrolidinamine, 1-(2-phenyl-4-quinazolinyl)-, (S)— are         excluded;     -   iv. when R¹ and R², taken together are unsubstituted         pyrrolidin-1-yl, ring A is unsubstituted phenyl, and x is 1,         then R³ is not 6-OMe or 6-OH;     -   v. when R¹ and R², taken together are unsubstituted         pyrrolidin-1-yl, ring A is unsubstituted phenyl, and x is 2,         then the two R³ groups are not 6-OMe and 7-OMe;     -   vi. when R¹ and R², taken together are unsubstituted         pyrrolidin-1-yl, then ring A is not unsubstituted         pyrrolidin-1-yl, optionally substituted piperazin-1-yl,         unsubstituted morpholin-1-yl; or unsubstituted piperidin-1-yl;     -   vii. when R¹ and R²; taken together are pyrrolidin-1-yl, x is 0         and ring A is unsubstituted phenyl, then the pyrrolidin-1-yl         group is not substituted at the 3-position with —OH or         2-methoxy-phenoxy;     -   viii. when R¹ and R², taken together are unsubstituted         pyrrolidin-1-yl, and x is 0, then ring A is not 2,3-xylyl,         3-methylphenyl, unsubstituted phenyl, 4-bromo-phenyl,         4-chloro-phenyl, 3-nitro-phenyl, unsubstituted pyrid-3-yl,         2,4-dichlorophenyl, 3,4-dichlorophenyl, 4-propoxyphenyl,         3-methylphenyl, 3,4,5-trimethoxyphenyl, 2-chlorophenyl,         unsubstituted pyrid-4-yl, 2-hydroxyphenyl, or         4-(1,1-dimethylethyl)phenyl;

c. when R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 6-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then:

-   -   i. when R¹ and R², taken together form an unsubstituted         morpholino ring, and ring A is unsubstituted phenyl, then x is         not 0, or if x is 1 or 2, then R³ is not: 6-fluoro,         6,7-dimethoxy, 6-nitro, 6-AcHN—, 6-methox, 6-NH2, 6-OCHN—, 6-OH,         6-AcMeN—, 6-TsHN—, 6-Me2N—, 7-OH, 6-amino-thiazol-2-yl,         6-NHCOCOOEt, or 6-(4-phenyl-amino-thiazol-2-yl);     -   ii. when R¹ and R², taken together form an unsubstituted         morpholino ring, and ring A is unsubstituted cyclohexyl,         unsubstituted pyrid-3-yl, unsubstituted 2-furyl, 2-fluorophenyl,         3-thienyl, benzofuran, pyridazine, phenyl substituted in one or         more of the 3, 4, or 5-position of the phenyl ring, and x is 1         or 2, then R³ is not 6-NH2, 6-OHCHN—, 6-OH, 7-OH, 6-MsHN—,         6-AcHN—, 6-fluoro, or 6-OMe;     -   iii. when R¹ and R², taken together, form a piperid-4-one,         piperid-4-ol, or thiomorpholino, or a dimethyl substituted         morpholino ring, ring A is unsubstituted phenyl, and x is 1,         then R³ is not 6-OH;     -   iv. when x is 0 and A is unsubstituted phenyl,         3,4,5-trimethoxyphenyl, or 3,4-dimethoxyphenyl, then R¹ and R²,         taken together is not optionally substituted piperidinyl or         optionally substituted piperazinyl;     -   v. when x is 2 or 3, and R³ is 6,7-diOMe, or 6,7,8-triOMe, then         R¹ and R², taken together is not optionally substituted         piperidin-1-yl, piperazin-1-yl, or morpholin-1-yl;     -   vi. when x is 0 and ring A is unsubstituted phenyl, then R¹ and         R², taken together is not optionally substituted or fused         piperazinyl;     -   vii. when x is 0 and ring A is phenyl optionally substituted in         one or more of the 3-, 4-, or 5-positions of the phenyl ring,         then R¹ and R², taken together is not optionally substituted         piperazin-1-yl, or morpholin-1-yl;     -   viii. when x is 0 and ring A is 2-F-phenyl, then R¹ and R²,         taken together is not 4-(2-Cl-phenyl)-piperazin-1-yl,         4-(3-Cl-phenyl)-piperazin-1-yl, or unsubstituted morpholin-1-yl;     -   ix. when x is 0 and ring A is 2-Cl-phenyl, then R¹ and R², taken         together is not unsubstituted morpholin-1-yl,         4-Me-piperazin-1-yl, 4-Et-piperazin-1-yl,         4-phenyl-piperazin-1-yl, or 4-CH₂Ph₂-piperazin-1-yl;     -   x. when x is 0 and ring A is 2-OH-phenyl, then R1 and R2, taken         together is not unsubstituted morpholin-1-yl,         4-(2-OMe-phenyl)-piperazin-1-yl, 4-CH2Ph-piperazin-1-yl,         4-Et-piperazin-1-yl, or 4-Me-piperazin-1-yl;     -   xi. when x is 0, x is 1 and R³ is 6-Br, or x is 2 and R³ is         6-7-diOMe, and ring A is optionally substituted 2- or 3-thienyl,         then R¹ and R², taken together is not 4-Ph-piperazin-1-yl,         4-(3-CF₃-phenyl)-piperazin-1-yl,         4-(2-OEt-phenyl)-piperazin-1-yl, 4-Me-piperazinyl, or         unsubstituted morpholin-1-yl;     -   xii when x is 0, and ring A is unsubstituted pyrid-3-yl or         pyrid-4-yl, then R¹ and R², taken together is not optionally         substituted morpholin-1-yl, or optionally substituted         piperazin-1-yl;     -   xiii. when x is 0, and ring A is optionally substituted         1H-imidazol-2-yl or 1H-imidazol-1-yl, then R¹ and R² taken         together is not unsubstituted morpholin-1-yl,         4-Me-piperazin-1-yl, or 4-CH₂CH₂OH-piperazin-1-yl;     -   xiv. when x is 0 and ring A is 5-NO₂-thiazol-2-yl, then R¹ and         R², taken together is not 4-Me-piperazin-1-yl;     -   xv. when x is 0 and ring A is 5-NO₂-2-furanyl, then R¹ and R²,         taken together is not 4-CH₂CH₂OH-piperazin-1-yl,         4-Me-piperazin-1-yl, or unsubstituted morpholin-1-yl;     -   xvi. when x is 1, R³ is 6-OH and ring A is unsubstituted phenyl,         then R¹ and R², taken together is not unsubstituted         morpholin-1-yl, or 4-Me-piperazin-1-yl;     -   xvii. when x is 0 and R¹ and R², taken together is unsubstituted         piperidinyl, then ring A is not 2-OH-phenyl, 4-OMe-phenyl,         4-F-phenyl, 4-NO₂-phenyl, pyrid-3-yl, pyrid-4-yl, 2-Cl-phenyl,         4-O_(n)Pr-phenyl, 3,4-dichlorophenyl, 2-F-phenyl, 4-Br-phenyl,         4-Cl-phenyl, 3-NO₂-phenyl, or 2,4-dichlorophenyl;     -   xviii. when x is 0, ring A is 4-Br-phenyl, 2-F-phenyl,         2-Cl-phenyl, 4-Cl-phenyl, 4-OnPr-phenyl, 2,4-dichlorophenyl,         3,4-dichlorophenyl, 4-Me-phenyl, 3-Me-phenyl, pyrid-3-yl,         pyrid-4-yl, 2-OH-phenyl, 4-NO₂-phenyl, 4-tBu-phenyl, then R¹ and         R², taken together is not 2-Me-piperidin-1-yl,         4-CH₂-Ph-piperidin-1-yl, 4-Me-piperidin-1-yl,         3-COOEt-piperidin-1-yl, 4-COOEt-piperidin-1-yl,         2-Et-piperidin-1-yl, 3-Me-piperidin-1-yl,         3,5-diMe-piperidin-1-yl, 4-CONH₂-piperidin-1-yl, (4-piperidinyl,         4-carboxamide)-piperidin-1-yl, 1,4-dioxa-8-azaspiro[4.5]decane,         3,4-dihydro-2(1H)-isoquinolinyl, or piperidin-4-one;     -   xix. when x is 1, R³ is 6-Br, 6-Cl, 6-OH, 6-OMe, or 6-Me and         ring A is 4-bromophenyl, 4-CH₂P(O)(OH)(OEt)phenyl, or         unsubstituted phenyl, then R¹ and R², taken together, is not         optionally substituted piperidinyl;     -   xx. when x is 2, and R³ is 6,7-dimethoxy, and A is unsubstituted         phenyl, then R¹ and R², taken together is not         1,4-dioxa-8-azaspiro[4.5]decane or         3,4-dihydro-2(1H)-isoquinolinyl;     -   xxi. when x is 3, and the three occurrences of R³ are 5-OAc,         6-OAc, and 8-piperidinyl, and ring A is unsubstituted phenyl,         then R¹ and R², taken together is not an unsubstituted         piperidinyl ring;     -   xxii. when x is 3 and the three occurrences of R³ are 6-Me,         7-COOEt, and 8-Me, and ring A is 2-Cl-phenyl, then R¹ and R²,         taken together, is not 4-phenyl-piperidin-1-yl,         4-(4-Cl-phenyl)-piperazin-1-yl, unsubstituted piperazin-1-yl,         4-CH₂Ph-piperazin-1-yl, 4(2-Cl-phenyl)piperazin-1-yl, or         4-COOEt-piperazin-1-yl;

c. when R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 7-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then:

-   -   i. Benzenesulfonamide,         2-methoxy-5-[2-[5-(2-phenyl-4-quinazolinyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]ethyl]-,         and bis(trifluoroacetate) 2,5-Diazabicyclo[2.2.1]heptane,         2-(2-phenyl-4-quinazolinyl)- are excluded;     -   ii. when x is 2 and both occurrences of R³ are OMe, and ring A         is 4-Cl-phenyl, then R¹ and R², taken together is not         unsubstituted hexahydro-1H-azepin-1-yl;     -   iii. when x is 0 and R¹ and R², taken together is unsubstituted         hexahydro-1H-azepin-1-yl, then ring A is not unsubstituted         phenyl, 4-F-phenyl, 4-NO₂-phenyl, pyrid-4-yl, 3,4-diCl-phenyl,         2-Cl-phenyl, 2,4-diCl-phenyl, 2,4-diCl-phenyl, 3-NO₂-phenyl,         4-Cl-phenyl, 4-O_(n)Pr-phenyl, 3-Me-phenyl, 3,4-OMe-phenyl,         3,4,5-OMe-phenyl, pyrid-3-yl, or 2-OH-phenyl;

d. when R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 8-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then:

-   -   i. Benzenesulfonamide,         2-methoxy-5-[2-[8-(2-phenyl-4-quinazolinyl)-3,8-diazabicyclo[3.2.1]oct-3-yl]ethyl]-,         bis(trifluoroacetate) 3,8-Diazabicyclo[3.2.1]octane,         3-(phenylmethyl)-8-(2-phenyl-4-quinazolinyl)-3,8-Diazabicyclo[3.2.1]octane,         8-(2-phenyl-4-quinazolinyl)-; Quinazoline,         2-(3-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-,         monohydrochloride; Quinazoline,         2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-,         monohydrochloride; Quinazoline,         2-(3-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-;         Quinazoline,         2-(4-methylphenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-;         and Quinazoline,         2-(4-nitrophenyl)-4-(1,3,3-trimethyl-6-azabicyclo[3.2.1]oct-6-yl)-         are excluded; and

e. when R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 9-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; then: piperazine, 1-[4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-6,7-dimethoxy-2-quinazolinyl]-4-(2-furanylcarbonyl)- is excluded.

In other embodiments, for compounds described directly above, the ring formed by R¹ and R² taken together is selected from:

wherein the ring formed by R¹ and R² taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, and z is 0-5.

In other embodiments, for compounds of formula I-A, R¹ and R² taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R¹ and R² taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin 1-yl (dd). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc).

For compounds described directly above, z is 0-5, and R⁴ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

In certain embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In still other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRCOOR′. In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

For compounds described directly above, in some embodiments, x is 0-4, and R³ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, x is 1 or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In still other embodiments, x is 1 or 2 and each R³ group is independently halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 or 2, and each R³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

For compounds described directly above, in certain embodiments, ring A is a group selected from:

In other embodiments, ring A is optionally substituted phenyl, 2-pyridyl, 3-pyridyl, or 4-pyridyl, or pyrrol-1-yl.

For compounds described directly above, in some embodiments, y is 0-5, q is 0-2, and R⁵ and R^(5a) groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy.

In still other embodiments, y is 0, and q is 1 and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the other occurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

In yet other embodiments, ring A is optionally substituted phenyl and compounds have the structure IA-i:

wherein:

y is 0-5;

q is 0-2; and

each occurrence of R^(5a) is independently an optionally substituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂.

In certain exemplary embodiments, the ring formed by R¹ and R² taken together is selected from:

wherein the ring formed by R¹ and R² taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, and z is 0-5.

In other embodiments, for compounds of formula IA-i, R¹ and R² taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R¹ and R² taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperidin1-yl (dd). In yet other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc).

For compounds of formula IA-i, z is 0-5, and R⁴ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl. In other embodiments, z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

In certain embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′. In certain other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yet other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In still other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRCOOR′. In yet other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. In certain other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COOR′. In certain other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certain other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds of formula IA-i, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

In some embodiments for compounds of formula IA-i, x is 0-4, and R³ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, x is 1 or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In yet other embodiments, x is 1 or 2 and each R³ group is independently halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.

In still other embodiments, x is 1 or 2, and each R³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet other embodiments x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In some embodiments for compounds of formula IA-i, y is 0-5, q is 0-2, and R⁵ and R^(5a) groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected from C₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy.

In still other embodiments, when ring A is phenyl, y is 0, and q is 1 and R^(5a) is F substituted at the 2-position of the phenyl ring. In yet other embodiments, when ring A is phenyl, y is 0, q is 1, and R^(5a) is OR′ substituted at the 2-position of the phenyl ring. In still other embodiments, when ring A is phenyl, y is 0, q is 1 and R^(5a) is OH substituted at the 2-position of the phenyl ring. In yet other embodiments, when ring A is phenyl, y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the other occurrence of R^(5a) is F, wherein OR′ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, when ring A is phenyl, y is 0, q is 2 and one occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.

In still other embodiments, for compounds of formula IA-i, q is 1 and R^(5a) is at the 2-position of the phenyl ring, and compounds have the structure IA-ii:

wherein:

a) the ring formed by R¹ and R² taken together is selected from:

and the ring formed by R¹ and R² taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, and z is 0-5;

b) wherein z is 0-5, and R⁴ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

c) wherein x is 0-4, and R³ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

d) wherein y is 0-5, and R⁵ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected from C₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl; and

e) R^(5a) is Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy.

In still other embodiments, for compounds of formula IA-ii: q is 1 and R^(5a) is at the 2-position of the phenyl ring, and compounds have the structure IA-ii:

wherein:

a) R¹ and R² taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), or piperazin-1-yl (cc);

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 1 or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-4, and R⁵ groups, when present, are each independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In still other embodiments, for compounds of formula IA-ii x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In still other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, OR′, —OH, —OCH₃, —OCH₂CH₃.

In yet other embodiments, R^(5a) is OR′. In still other embodiments, R^(5a) is F.

In still other exemplary embodiments compounds have formula IA-ii:

wherein:

a) R¹ and R² taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl piperidin1-yl (dd), or piperazin-1-yl (cc);

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 1, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —OH, or —OCH₃;

d) y is 0 or 1, and R⁵ groups, when present, are each independently Cl, Br, F, CF₃, Me, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂; and

e) R^(5a) is F, —OR′, or NHSO₂R′.

In some embodiments for compounds described directly above, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂; or NRCOR′.

In yet other embodiments, R^(5a) is OR′ and x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, R^(5a) is OR′ and x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, R^(5a) is OH and x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, R^(5a) is OH and x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, R^(5a) is F and x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, R^(5a) is F and x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In still other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperidin 1-yl (dd). In yet other embodiments, for compounds, of formula IA-ii, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc).

In certain embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′. In certain other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yet other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In still other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRCOOR′. In yet other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. In certain other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COOR′. In certain other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certain other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds of formula IA-ii, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or NaV1.7.

II. Compounds of Formula IA-ii

wherein R¹ and R² are each independently an optionally substituted group selected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹ and R² are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;

x is 0-4;

y is 0-4;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X) is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

R^(5a) is an optionally substituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, for compounds described directly above,

a. when x is 0, R¹ is hydrogen, and R^(5a) is Cl, Me, CF₃, Br, or F, then R² is not —(CH₂)₂-4-Cy¹, —SO₂CH₂Cy¹, or —CH₂SO₂Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-8-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

b. when x is 0, and R^(5a) is Cl, Me, NO₂, or OH, then:

-   -   i. when R¹ is hydrogen, R² is not Me, iBu, nBu, —COCH₃,         —CH₂COOEt, —CH₂COOMe, —CH₂CH₂OH, iPr, —CH₂-pyridyl, —CH₂Ph,         —(CH₂)₃NH₂, —(CH₂)₂-moropholinyl, or —CH₂CH₂Ph;     -   ii. R¹ and R² are not simultaneously Et or Me; and     -   iii. when R¹ is Et, then R² is not 4-Me-phenyl, 4-OMe-phenyl, or         2-Me-phenyl;

c. when x is 1 and R³ is 6-Cl, or 7-F, or x is 0 and R^(5a) is —OPr_(n), or Cl, then when R¹ is hydrogen, R² is not —(CH₂)₂-morpholino, or —CH₂(benzofuran); and

d. when x is 2 and one occurrence of R³ is 6-OMe and the other occurrence of R³ is 7-OMe, and R^(5a) is F, then when R¹ is hydrogen, R² is not —(CH₂)₃N(CH₃)₂;

In certain other embodiments, for compounds described directly above,

a) one of R¹ or R² is hydrogen, and the other of R¹ and R² is selected from:

-   -   i) Cy¹ wherein Cy¹ is bonded directly to the nitrogen atom or is         bonded through an optionally substituted C₁₋₄aliphatic group,         wherein one or more methylene units in the C₁₋₄aliphatic group         are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—,         —CONR—, —SO₂NR—, or —NRSO₂—; or     -   ii) an optionally substituted C₁₋₄aliphatic group, wherein one         or more methylene units, in the C₁₋₄aliphatic group are         optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,         —SO₂NR—, or —NRSO₂—; or

b) R¹ and R² are each independently selected from Cy¹, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In other embodiments Cy¹ is:

In still other embodiments, for compounds described directly above, R¹ is hydrogen or an optionally substituted C₁-C₄aliphatic group and R² is —CHR-Cy¹, wherein R is hydrogen or C₁-C₄alkyl, and Cy¹ is:

In yet other embodiments, R¹ and R² groups are each independently an optionally substituted C₁₋₄aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.

For compounds described directly above, z is 0-5, and R⁴ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In other embodiments, z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

In still other embodiments, for compounds described directly above, x is 0-4, and R³ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, for compounds described directly above, x is 1 or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In still other embodiments, x is 1 or 2 and each R³ group is independently halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′.

In yet other embodiments, x is 1 or 2, and each R³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN.

In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃.

In yet other embodiments, R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

For compounds described directly above, y is 0-4, q is 0-2, and R⁵ and R^(5a) groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl

In other embodiments, y is 0-4, and q is 1 or 2, and each occurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy.

In still other embodiments, y is 0, and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵ is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.

In still other embodiments for compounds of formula IA-ii described directly above:

a) one of R¹ or R² is hydrogen, and the other of R¹ and R² is selected from Cy¹, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—, or an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R² are each independently selected from an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or Cy¹ wherein Cy¹ is bonded to the nitrogen atom directly or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 0, 1, or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-4, and R⁵ groups, when present, are each independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In other embodiments, for compounds described directly above, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In yet other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃.

In still other embodiments, y is 0, and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵ is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.

In still other embodiments for compounds of formula IA-ii described above:

a): one of R¹ or R² is hydrogen, and the other of R¹ and R² is selected from Cy¹, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—, or an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R² are each independently selected from an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or Cy¹ wherein Cy¹ is bonded to the nitrogen atom directly or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; and Cy¹ is selected from:

or R¹ and R² are each independently an optionally substituted C₁₋₄aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 0, 1, or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-4, and R⁵ groups, when present, are each independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In yet other embodiments for compounds described directly above, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet other embodiments,

x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In still other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃.

In still other embodiments, y is 0, and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵ is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.

For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or NaV1.7.

III. Compounds of Formula IA-i

or a pharmaceutically acceptable salt thereof,

wherein R¹ and R² are each independently an optionally substituted group selected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹ and R², are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;

x is 1 and R³ is substituted at either the 6- or 7-position of the quinazoline ring;

y is 0-4;

q is 0, 1 or 2;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO, —CO—, —COCO—, —CONR—, NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X) is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R^(5a) is independently an optionally substituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, for compounds described directly above:

a) when R³ is at the 7-position of the quinazoline ring then:

-   -   i) when R³ is Cl or Me, ring A is unsubstituted naphthyl, and R¹         is hydrogen, then R² is not —(CH₂)₃NMe₂;     -   ii) when R³ is Cl, the sum of q and y is 1 and the phenyl ring         is substituted at the 4-position with Br, and R¹ is hydrogen,         then R² is not Cy¹, wherein Cy¹ is bonded to the nitrogen atom         through an optionally substituted C₁₋₄aliphatic group, wherein         one or more methylene units in the C₁₋₄aliphatic group are         optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,         —SO₂NR—, or —NRSO₂—;     -   iii) when R³ is Cl or OMe, the sum of q and y is 1 and the         phenyl ring is substituted at the 4-position with either OMe or         Cl, and R¹ is hydrogen, then R² is not —CH(CH₃)(CH₂)₃N(Et)₂;     -   iv) when R³ is Me, OMe, or NO², and q and y are 0, then R¹ and         R² are not both methyl;     -   v) when R³ is OMe, q and y are 0, and R¹ is hydrogen, then R² is         not —SO₂(4-Me-phenyl);     -   vi) when R³ is F, the sum of q and y is 1 and the phenyl ring is         substituted at the 2-position with Cl, and R¹ is hydrogen, then         R² is not —(CH₂)morpholino; and

b) a) when R³ is at the 6-position of the quinazoline ring then:

-   -   i) when R³ is NH₂, Me, Cl, Br, —NHAc, the sum of q and y is 1         and the phenyl ring is substituted at the 4-position with F, or         ring A is naphthyl, and R¹ is hydrogen, then R² is not         —(CH₃)₃₋₄N(R′)₂;     -   ii) when R³ is —OCH₂Ph, or OH, and q and y are 0, then when R¹         is hydrogen, R² is not Me, nBu, or —(CH₂)₂-morpholino, or R¹ and         R² are not simultaneously Me or Et;     -   iii) when R³ is Me or Cl, and the sum of q and y are 1, then the         phenyl ring is not substituted in the 4-position with Br;     -   iv) when R³ is Cl, q and y are 0, and R¹ is hydrogen, then R² is         not —SO₂(4-Me-phenyl);     -   v) when R³ is OMe, and q and y are 0, and R¹ is hydrogen, then         R² is not —CH₂CH₂OH or —CH₂CH₂pyrrolidinyl;     -   vi) when R³ is Cl or Br, the sum of q and y is 1, and the phenyl         ring is substituted in the 4-position with —CH₂PO(OR′)₂, then R¹         is not hydrogen when R² is -Me, or R¹ and R² are not         simultaneously Me or Et;     -   vii) when R³ is OH and q and y are 0, then R¹ and R² are not         simultaneously —CH₂CH₂OMe;     -   viii) when R³ is Cl, the sum of q and y is 1 and the phenyl ring         is substituted in the 2-position with OnPr, and R¹ is hydrogen,         then R² is not —CH₂(1,3-benzodioxol);     -   ix) when R³ is OMe, OH, Br, C₁, NO₂, Me, and q and y are 0, then         when R¹ is hydrogen, R² is not Me, —CH₂CH₂COOMe, —CH₂COOMe, or         —(CH₂)₃CH₃, or R¹ and R² are not simultaneously Me; and     -   x) when R³ is Cl, the sum of q and y is 1 and the phenyl ring is         substituted in the 4-position with Cl, then R¹ and R² are not         simultaneously Me or iPr.

In certain other embodiments, for compounds described directly above:

a) one of R¹ or R² is hydrogen, and the other of R¹ and R² is selected from:

-   -   i) Cy¹ wherein Cy¹ is bonded directly to the nitrogen atom or is         bonded through an optionally substituted C₁₋₄aliphatic group,         wherein one or more methylene units in the C₁₋₄aliphatic group         are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—,         —CONR—, —SO₂NR—, or —NRSO₂—; or     -   ii) an optionally substituted C₁₋₄ aliphatic group, wherein one         or more methylene units in the C₁₋₄aliphatic group are         optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,         —SO₂NR—, or —NRSO₂—; or

b) R¹ and R² are each independently selected from Cy¹, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In still other embodiments, Cy¹ is:

In yet other embodiments, R¹ is hydrogen or an optionally substituted C₁-C₄aliphatic group and R² is —CHR-Cy¹, wherein R is hydrogen or C₁-C₄alkyl, and Cy¹ is:

In yet other embodiments, R¹ and R² groups are each independently an optionally substituted C₁₋₄aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.

In still other embodiments, for compounds described directly above, z is 0-5, and R⁴ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl

In yet other embodiments, z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

In still other embodiments, for compounds described directly above, R³ is halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In still other embodiments, R³ is halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′. In yet other embodiments, R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In still other embodiments, R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In still other embodiments for compounds described directly above, y is 0-5, q is 0-2, and R⁵ and R^(5a) groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy.

In still other embodiments, y is 0, and R^(5a) is F. In yet other embodiments y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵ is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.

In still other embodiments, R³ is substituted at the 6-position of the quinazoline ring, q is 1, and y is 0, and compounds have formula III:

In certain embodiments, for compounds described above,

a) R¹ and R² are each independently an optionally substituted group selected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹ and R², are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and

d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In certain other embodiments, for compounds described directly above R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, R³ is —CON(R′)₂, or NRCOR′. In still other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃.

In still other embodiments, y is 0, and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH.

In certain other embodiments, for compounds described directly above:

a) Cy¹ is:

or R¹ and R² are each independently an optionally substituted C₁₋₄aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)O₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and

d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In certain embodiments, for compounds described directly above R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —OCH₂CH₃, or —CN. In other embodiments, R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, R³ is —CON(R′)₂, or NRCOR′. In yet other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃. In still other embodiments, y is 0, and R^(5a) is F. In yet other embodiments y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH.

In yet other embodiments, R³ is substituted at the 7-position of the quinazoline ring, q is 1, and y is 0, and compounds have formula IV:

a) wherein R¹ and R² are each independently an optionally substituted group selected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹ and R², are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and

d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In certain embodiments, for compounds described directly above, R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In other embodiments, R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, R³ is —CON(R′)₂, or NRCOR′. In yet other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃. In still other embodiments, y is 0, and R^(5a) is F. In yet other embodiments y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH.

In certain other embodiments, for compounds described directly above:

a) Cy¹ is:

or R¹ and R² are each independently an optionally substituted C₁₋₄aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy; and

d) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In certain other embodiments, for compounds described directly above R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In other embodiments, R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, R³ is —CON(R′)₂, or NRCOR′. In yet other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, or —OCH₂CH₃. In still other embodiments, y is 0, and R^(5a) is F. In yet other embodiments y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH.

For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or NaV1.7.

IV. Compounds of Formula V

wherein R¹ and R² are each independently an optionally substituted group selected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12-membered monocyclic or bicyclic saturated or partially unsaturated ring having 0-3 additional heteroatoms independently selected from nitrogen, sulfur, or oxygen; wherein R¹ and R², or the ring formed by R¹ and R² taken together, are each optionally and independently substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;

x is 0-4;

y is 0-2;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X) is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

R^(5a) is an optionally substituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group; and each occurrence of R is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

In certain embodiments, for compounds described directly above, when x is 1 and R³ is 6-OMe, R¹ is hydrogen, and y and q are both 0, then R² is not —CH₂CH₂OCH₂CH₂OH or the monomethanesulfonate salt.

In certain other embodiments, for compounds described directly above,

a) one of R¹ or R² is hydrogen, and the other of R¹ and R² is selected from:

-   -   i) Cy¹ wherein Cy¹ is bonded directly to the nitrogen atom or is         bonded through an optionally substituted C₁₋₄aliphatic group,         wherein one or more methylene units in the C₁₋₄aliphatic group         are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—,         CONR—, —SO₂NR—, or —NRSO₂—; or     -   ii) an optionally substituted C₁₋₄aliphatic group, wherein one         or more methylene units in the C₁₋₄aliphatic group are         optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,         —SO₂NR—, or —NRSO₂—; or

b) R¹ and R² are each independently selected from Cy¹, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO—, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—.

In other embodiments, Cy¹ is:

In still other embodiments, R¹ is hydrogen or an optionally substituted C₁-C₄aliphatic group and R² is —CHR-Cy¹, wherein R is hydrogen or C₁-C₄alkyl, and Cy¹ is:

In still other embodiments, R¹ and R² groups are each independently an optionally substituted C₁₋₄aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.

In yet other embodiments for compounds described directly above, R¹ and R², taken together with the nitrogen atom to which they are bound, form an optionally substituted 3-12 membered heterocyclyl ring having 1-3 heteroatoms independently selected from nitrogen or oxygen and form a 3-12 membered heterocyclyl group selected from:

wherein the ring formed by R¹ and R² taken together, is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, and z is 0-5.

In other embodiments, for compounds of formula I-A, R¹ and R² taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin 1-yl (dd), piperazin-1-yl (cc), or morpholin-4-yl (ee). In other embodiments, for compounds of formula I-A, R¹ and R² taken together are optionally substituted azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), or piperazin-1-yl (cc). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin1-yl (dd). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc).

In still other embodiments, for compounds described directly above, z is 0-5, and R⁴ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

In certain embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff), wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In still other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRCOOR′. In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

In still other embodiments, x is 0-4, and R³ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl. In yet other embodiments, x is 1 or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In still other embodiments, x is 1 or 2 and each R³ group is independently halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′. In yet other embodiments, x is 1 or 2, and each R³ group is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In still other embodiments for compounds described directly above, y is 0-2, q is 0-2, and R⁵ and R^(5a) groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In yet other embodiments, y is 0-2, and q is 1 or 2, and each occurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy.

In still other embodiments, y is 0, and q is 1 and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the other occurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

In still other embodiments:

a) R¹ and R² taken together is an optionally substituted ring selected from azetidin-1-yl (jj), pyrrolidin-1-yl (ff), piperidin1-yl (dd), or piperazin-1-yl (cc); one of R¹ or R² is hydrogen, and the other of R¹ and R² is selected from Cy¹, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—, or an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or R¹ and R² are each independently selected from an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; or Cy¹ wherein Cy¹ is bonded to the nitrogen atom directly or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 0, 1, or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-2, and R⁵ groups, when present, are each independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ff). In still other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin1-yl (dd). In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc).

In certain embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 or 2 and at least one occurrence of R⁴ is —NRSO₂R′, —NRCOOR′, or —NRCOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRSO₂R′. In other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted azetidin-1-yl (jj), wherein z is 1 and R⁴ is —NRCOR′. In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted pyrrolidin-1-yl (ft), wherein z is 1 or 2 and R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In still other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 or 2 and at least one occurrence of R⁴ is Cl, Br, F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′, —NRSO₂R′, —NRCOOR′, or —OCON(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is F, CF₃, CH₃, —CH₂CH₃, —OR′, or —CH₂OR′. In other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRSO₂R′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperidin-1-yl (dd), wherein z is 1 and R⁴ is —NRCOOR′. In yet other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 or 2 and at least one occurrence of R⁴ is —SOR′, —CON(R′)₂, —SO₂N(R′)₂, —COR′, or —COOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COOR′. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —CON(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —SO₂N(R′)₂. In certain other embodiments, for compounds of formula I-A, R¹ and R², taken together is optionally substituted piperazin-1-yl (cc), wherein z is 1 and R⁴ is —COR′.

In yet other embodiments for compounds described directly above, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃. In still other embodiments, y is 0, and q is 1 and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the other occurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

In certain embodiments, for compounds described directly above,

a) Cy¹ is:

or R¹ and R² are each independently an optionally substituted C₁₋₄aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl;

b) z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl;

c) x is 0, 1, or 2, and each occurrence of R³ is independently Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy;

d) wherein y is 0-5, and R⁵ groups, when present, are each independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy; and

e) R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), or —COCH₃.

In yet other embodiments for compounds described directly above, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —OCH₂CH₃, or —CN. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In yet other embodiments, x is 1 and R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet other embodiments, x is 1 and R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet other embodiments, R^(5a) is Cl, F, CF₃, Me, Et, —OH, —OCH₃, —OCH₂CH₃. In still other embodiments, y is 0, and q is 1 and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OR′ and the other occurrence of R^(5a) is F. In yet other embodiments, y is 0, q is 2 and one occurrence of R^(5a) is OH and the other occurrence of R^(5a) is F.

For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or NaV1.7.

V. Compounds of Formula I-B-i

or a pharmaceutically acceptable salt thereof,

wherein R¹ is selected from C₁₋₆aliphatic, Cy¹, wherein Cy¹ is a 5-7-membered monocyclic aryl ring or an 8-10-membered bicyclic aryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or is a 3-12-membered saturated or partially unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein Cy¹ is bonded directly to the nitrogen atom or is bonded through an optionally substituted C₁₋₄aliphatic group, wherein one or more methylene units in the C₁₋₄aliphatic group are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—, —SO₂NR—, or —NRSO₂—; wherein R¹ is optionally substituted at one or more substitutable carbon, nitrogen, or sulfur atoms with z independent occurrences of —R⁴, wherein z is 0-5;

x is 0-4;

y is 0-4;

each occurrence of R³, R⁴, and R⁵ is independently Q-R^(X); wherein Q is a bond or is a C₁-C₆ alkylidene chain wherein up to two non-adjacent methylene units of Q are optionally and independently replaced by —NR—, —S—, —O—, —CS—, —CO₂—, —OCO—, —CO—, —COCO—, —CONR—, —NRCO—, —NRCO₂—, —SO₂NR—, —NRSO₂—, —CONRNR—, —NRCONR—, —OCONR—, —NRNR—, —NRSO₂NR—, —SO—, —SO₂—, —PO—, —PO₂—, —OP(O)(OR)—, or —POR—; and each occurrence of R^(X) is independently selected from —R′, ═O, ═NR′, halogen, —NO₂, —CN, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂;

each occurrence of R^(5a) is independently an optionally substituted C₁-C₆aliphatic group, halogen, —OR′, —SR′, —N(R′)₂, —NR′COR′, —NR′CON(R′)₂, —NR′CO₂R′, —COR′, —CO₂R′, —OCOR′, —CON(R′)₂, —OCON(R′)₂, —SOR′, —SO₂R′, —SO₂N(R′)₂, —NR′SO₂R′, —NR′SO₂N(R′)₂, —COCOR′, —COCH₂COR′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, or —OPO(R′)₂; and

each occurrence of R is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group; and each occurrence of R′ is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R and R′, two occurrences of R, or two occurrences of R′, are taken together with the atom(s) to which they are bound to form an optionally substituted 3-12 membered saturated, partially unsaturated, or fully unsaturated monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

For compounds described directly above, in certain embodiments,

a) when R^(5a) is Me, Cl, or OMe, and x is 0, then R¹ is not Et or Me;

b) when R^(5a) is Cl, x is 3, and the three occurrences of R³ are 6-Me, 7-COOEt, and 8-Me, then R¹ is not —(CH₂)₂piperidin-1-yl;

c) when R^(5a) is Me, x is 1 and R³ is NO₂ or NH₂, then R¹ is not Et;

d) when R^(5a) is OH, NHMe, or N(NO)Me, and x is 0, then R¹ is not Et, Me or —CH₂CH═CH₂;

e) when R^(5a) is NH², and x is 0, then R¹ is not —COCH₃;

f) when R^(5a) is Cl or Me, and y is 0 or 1 and when y is 1, R⁵ is 4-Cl, and x is 0, then R¹ is not 4-CN-phenyl, 4-Me-phenyl, 4-OMe-phenyl, 4-Cl-phenyl, 4-NO₂-phenyl, —CH₂CH₂NHMe, Et, Me, 4-COOMe-phenyl, —CH₂Ph, iPr, 2-Me-phenyl, 4-phenyl-phenyl, or —CH₂CH═CH₂.

For compounds described directly above, in certain other embodiments,

a) R¹ is selected from:

-   -   i) Cy¹ wherein Cy¹ is bonded directly to the nitrogen atom or is         bonded through an optionally substituted C₁₋₄aliphatic group,         wherein one or more methylene units in the C₁₋₄aliphatic group         are optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—,         —CONR—, —SO₂NR—, or —NRSO₂—; or     -   ii) an optionally substituted C₁₋₄aliphatic group, wherein one         or more methylene units in the C₁₋₄aliphatic group are         optionally replaced with —NR—, —O—, —COO, —OCO—, —NRCO—, —CONR—,         —SO₂NR—, or —NRSO₂—.

For compounds described directly above, in certain embodiments Cy¹ is,

In other embodiments, R¹ is —CHR-Cy¹, wherein R is hydrogen or C₁-C₄alkyl, and Cy¹ is:

In still other embodiments, R¹ is an optionally substituted C₁₋₄aliphatic group and are each independently selected from optionally substituted methyl, ethyl, cyclopropyl, n-propyl, propenyl, cyclobutyl, (CO)OCH₂CH₃, (CH₂)₂OCH₃, CH₂CO)OCH₂CH₃, CH₂(CO)OCH₃, CH(CH₃)CH₂CH₃, or n-butyl.

In yet other embodiments, z is 0-5, and R⁴ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, z is 0-5 and R⁴ groups are each independently Cl, Br, F, CF₃, CH₃, —CH₂CH₃, CN, —COOH, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂(CH₂)₃CH₃, —SO₂CH(CH₃)₂, —SO₂N(CH₃)₂, —SO₂CH₂CH₃, —C(O)OCH₂CH(CH₃)₂, —C(O)NHCH₂CH(CH₃)₂, —NHCOOCH₃, —C(O)C(CH₃)₃, —COO(CH₂)₂CH₃, —C(O)NHCH(CH₃)₂, —C(O)CH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, C₁₋₄alkoxy, phenyl, phenyloxy, benzyl, benzyloxy, —CH₂cyclohexyl, pyridyl, —CH₂pyridyl, or —CH₂thiazolyl.

In yet other embodiments, R³ is halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, R³ is Cl, Br, F, CF₃, —OCF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —NHCOCH(CH₃)₂, —SO₂NH₂, —CONH(cyclopropyl), —CONHCH₃, —CONHCH₂CH₃, or an optionally substituted group selected from -piperidinyl, piperizinyl, morpholino, phenyl, phenyloxy, benzyl, or benzyloxy.

In yet other embodiments, R³ is halogen, CN, optionally substituted C₁-C₆alkyl, OR′, N(R′)₂, CON(R′)₂, or NRCOR′. In still other embodiments, R³ is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In still other embodiments, R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —CONHCH₃, —CONHCH₂CH₃, —CONH(cyclopropyl), —OCH₃, —NH₂, —OCH₂CH₃, or —CN. In yet other embodiments, R³ is at the 6-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In still other embodiments, R³ is at the 7-position of the quinazoline ring and is —Cl, —CH₃, —CH₂CH₃, —F, —CF₃, —OCF₃, —OCH₃, or —OCH₂CH₃. In other embodiments, R³ is at the 6-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′. In yet other embodiments, R³ is at the 7-position of the quinazoline ring and is —CON(R′)₂, or NRCOR′.

In yet other embodiments, for compounds described directly above, y is 0-5, q is 0-2, and R⁵ and R^(5a) groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —NRCOR′, —CON(R′)₂, —S(O)₂N(R′)₂, —OCOR′, —COR′, —CO₂R′, —OCON(R′)₂, —NR′SO₂R′, —OP(O)(OR′)₂, —P(O)(OR′)₂, —OP(O)₂OR′, —P(O)₂OR′, —PO(R′)₂, —OPO(R′)₂, or an optionally substituted group selected from C₁₋C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl.

In still other embodiments, y is 0-5, and q is 1 or 2, and each occurrence of R^(5a) is independently Cl, Br, F, CF₃, Me, Et, CN, —COOH, —NH₂, —N(CH₃)₂, —N(Et)₂, —N(iPr)₂, —O(CH₂)₂OCH₃, —CONH₂, —COOCH₃, —OH, —OCH₃, —OCH₂CH₃, —CH₂OH, —NHCOCH₃, —SO₂NH₂, —SO₂NHC(CH₃)₂, —OCOC(CH₃)₃, —OCOCH₂C(CH₃)₃, —O(CH₂)₂N(CH₃)₂, 4-CH₃-piperazin-1-yl, OCOCH(CH₃)₂, OCO(cyclopentyl), —COCH₃, optionally substituted phenoxy, or optionally substituted benzyloxy.

In still other embodiments, y is 0, and R^(5a) is F. In yet other embodiments, y is 0, q is 1, and R^(5a) is OR′. In still other embodiments, y is 0, q is 1 and R^(5a) is OH. In yet other embodiments, y is 1, R^(5a) is OR′ and R⁵ is F, wherein OR′ is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring. In yet other embodiments, y is 1, R^(5a) is OH and R⁵ is F, wherein OH is substituted at the 2-position of the phenyl ring and F is substituted at the 6-position of the phenyl ring.

For compounds described in this section above, in general, compounds are useful as inhibitors of ion channels, preferably voltage gated sodium channels and N-type calcium channels. In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or NaV1.7.

Representative examples of compounds as described above and herein are set forth below in Table 2.

TABLE 2 Examples of Compounds of Formula I: Com- pound Cmpd # 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

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4. General Synthetic Methodology:

The compounds of this invention may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general scheme below, and the preparative examples that follow.

Scheme A below depicts general conditions for the synthesis of compounds of formula IA where X is NR². In general, the useful intermediate iii can be obtained by condensing a benzoylchloride with an anthranilamide.

Reaction of i and ii (step a) using K₂CO₃ and ether under reflux conditions, and subsequent treatment with 5% aq. NaOH under reflux conditions yields intermediate iii. Reaction of intermediate iii with POCl₃ to generate the 4-chloro compound, and subsequent reaction with i) N,N-dimethylaniline in benzene under reflux conditions; ii) BBr₃, CH₂Cl₂, −78° C.; and iii) R¹R²NH, in THF/CH₂Cl₂ at room temperature yields the desired product IA.

Reaction of i and ii (step a) using triethylamine and 1,4-Dioxane under ambient conditions yields intermediate iii. Reaction of intermediate iii (step b) with 0.5M solution of ammonia in 1,4-Dioxane, triethylamine and BOP reagent was stirred at ambient temperature for 16 h to yield intermediate iv. Treatment of iv with 5% aq. NaOH under reflux conditions yields intermediate v. Treatment of v with POCl₃ to generate the 4-chloro compound, and subsequent reaction with i) N,N-dimethylaniline in benzene under reflux conditions; ii) BBr₃, CH₂Cl₂, −78° C.; and iii) R¹R²NH, in THF/CH₂Cl₂ at room temperature yields the desired product IA.

Reaction of i and ii (step a) using pyridine yields intermediate iii. Treatment of iii with 5% aq. NaOH under reflux conditions yields intermediate iv. Reaction of intermediate iv with POCl₃ to generate the 4-chloro compound, and subsequent reaction with i) N,N-dimethylaniline in benzene under reflux conditions; ii) BBr₃, CH₂Cl₂, −78° C.; and iii) R¹R²NH, in THF/CH₂Cl₂ at room temperature yields the desired product IA.

Schemes D and E below depict the synthesis of a variety of useful anthranilimides:

Reaction of i (step a) with chloral hydrate in the presence of hydroxylamine hydrochloride yields isatin ii. Treatment of ii with basic hydrogen peroxide gives iii (step b), useful as shown in Scheme D.

Reaction of i (step a) with Boc anhydride yields ii. Subsequent metalation of ii with butyl lithium at low temperature and reaction with CO₂ yields the N-protected anthranilic acid (step b). Boc removal with TFA yields the anthranilic acid iii, useful as shown in Scheme E.

Reaction of isatoic anhydrides i (step a) with aqueous ammonium hydroxide yields ii, useful as shown in Scheme F.

(step a) i) Treatment of i in water with AcOH and KOCN 0° C. to room temperature for 24 h, and subsequent reaction with ii) NaOH followed by acidification with HCl yields intermediate ii. (step b) Treatment of ii with POCl₃ and triethylamine under reflux conditions yields intermediate iii. (step c) Treatment of iii with R¹R²NH, in THF/CH₂Cl₂ 0° C. to room temperature yields intermediate iv.

Reaction of intermediate i (step a) with POCl₃ generates the 2,4-dichloro compound ii. Reaction of intermediate ii (step b) with R₁—NH—R₂, and Et₃N, in CH₂Cl₂ yields amine iii. Reaction of intermediate iii (step c) with an NH containing heterocycle, NaH, and THF generates iv. Reaction of intermediate iii (step d) with LiHMDS, Pd₂(dba)₃, 2-(dicyclohexyl)phosphinobiphenyl, and THF yields diamine v. Reaction of intermediate v (step e) with a substituted 2,5-dimethoxytetrahydrofuran, in AcOH generates vi. Reaction of intermediate v (step with ClCO—CH₂—(CH₂)_(n)—CH₂—Cl, Et₃N, and p-dioxane generates vii. Reaction of intermediate iii (step g) with a cyclic anhydride, and p-dioxane generates viii.

Reaction of intermediate i (step a) with POCl₃ and subsequent treatment with BBr₃, CH₂Cl₂, at −78° C. generates the 4-chloro compound ii. Reaction of intermediate ii (step b) with R′—NH—R²—X(R′″)H, and Et₃N, in CH₂Cl₂ yields iii. Reaction of intermediate iii (step c) with R′N(R″)X—SO₂Cl, and Et₃N, in CH₂Cl₂ generates iv. Reaction of intermediate iii (step d) with R′—SO₂Cl, and Et₃N, in CH₂Cl₂ generates v. Reaction of intermediate iii (step e) with R′—CO₂Cl, and Et₃N, in CH₂Cl₂ or with phosgene, and R′(R″)XH generates vi. Reaction of intermediate iii (step f) with R′COCl, Et₃N, in CH₂Cl₂ generates vi. Reaction of intermediate iii (step g) with electrophiles in the presence of Et₃N (organic halide electrophiles) or NaBH(OAc)₃ (aldehyde and ketone electrophiles) yields viii.

Reaction of i with ii in dichloromethane under microwave irradiation at 150° C. yields product iii.

Conditions: (a) for M=Li: s-BuLi, TMEDA, THF, −78° C.; for M=ZnX: i. s-BuLi, TMEDA, THF, −78° C.; ii. ZnCl₂; for M=MgX: Mg, THF, reflux. (b) i. RSSR; ii. H₂O₂ (n=1) or KMnO₄ (n=2). (c) R¹R²C═O, THF, −78° C. to RT. (d) CO₂, THF, −78° C. to RT. (e) for R¹═H: R²NCO; others: R¹R²COCl, THF. (f) i. H₂C═O; ii. PBr₃; iii. R¹R²NH. (g) Het-OTf, Ni(acac)₂, PPh₃, MeMgBr, THF, RT. (h) is B(OMe)₃; ii. ArX (X=halogen), Pd(PPh₃)₄, NaOEt, toluene, 80° C. (i) i. SOCl₂, CH₂Cl₂; ii. R¹Sn(R)₃, Pd(PPh₃)₄, toluene; iii. R¹MgX, THF. (j) i. SOCl₂, CH₂Cl₂; ii. R¹R²NH, THF. (k) LiAlH₄, THF.

Conditions: (a) For M=Li: s-BuLi, TMEDA, THF, −78° C.; for M=ZnX: i. s-BuLi, TMEDA, THF, −78° C.; ii. ZnCl₂; for M=MgX: Mg, THF, reflux. (b) i. RSSR; ii. H₂O₂ (n=1) or KMnO₄ (n=2). (c) R′R²C═O, THF, −78° C. to RT. (d) CO₂, THF, −78° C. to RT. (e) for R¹═H: R²NCO; others: R¹R²COCl, THF. (f) i. H₂C═O; ii. PBr₃; iii. R¹R²NH. (g) Het-OTf, Ni(acac)₂, PPh₃, MeMgBr, THF, RT. (h) for R¹=Aryl: i. B(OMe)₃; ii. ArX (X=halogen), Pd(PPh₃)₄, NaOEt, toluene, 80° C. for R¹=alkyl: R¹I, THF, −78° C. to RT. (i) i. SOCl₂, CH₂Cl₂; ii. R¹Sn(R)₃, Pd(PPh₃)₄, toluene; iii. R²MgX, THF. (j) i. SOCl₂, CH₂Cl₂; ii. R¹R²NH, THF. (k) LiAlH₄, THF. (l) ArXB(OR)₂, Pd(PPh₃)₄, NaOEt, toluene, 80° C.

Treatment of i with ii using palladium catalyzed conditions (step a) Pd(dppf)Cl₂, KOAc, in DMSO or DMF at 84° C. for 2-6 hours yields intermediate iii. Reaction of intermediate iii with intermediate iv using palladium cross coupling conditions (step b) Pd(dppf)Cl2 or (Ph₃P)₄Pd, K₂CO₃, DMF:H₂O (4:1) under microwave irradiation at 170° C. for 6 minutes yields compound v.

Treatment of i with t-BuLi at −78° C., followed by addition of solid CO₂ and warming to room temperature yield carboxylate ii. The carboxylate in ii can be retained or utilized for reactions characteristic of the functional group.

Palladium catalyzed cross coupling of i with the appropriate amine in toluene (80° C.) yields ii.

Conditions: (a) R⁴COCl, pyridine, CH₂Cl₂, 0° C., then RT.

Reaction of i with iia or iib (step a), treatment with triethylamine in THF/CH₂Cl₂ at room temperature yields compounds iii and v respectively. Treatment of iii (step b) with i) NaH in THF 0° C., then reaction with electrophiles at 0° C. to room temperature yields compound Iv.

Although certain exemplary embodiments are depicted and described above and herein, it will be appreciated that a compounds of the invention can be prepared according to the methods described generally above using appropriate starting materials, and according to methods known in the art. For example, in certain embodiments, compounds as described herein wherein R¹ is hydrogen, and R² is pyrazolyl, exemplary procedures and compounds can be found in WO02/22607, WO 02/22604, WO 02/066461, WO 02/22601, WO 02/22603, WO 02/22608, WO 02/022605, or WO 02/22602.

5. Uses, Formulation and Administration

Pharmaceutically Acceptable Compositions

As discussed above, the present invention provides compounds that are inhibitors of voltage-gated sodium ion channels and/or calcium channels, and thus the present compounds are useful for the treatment of diseases, disorders, and conditions including, but not limited to acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, and incontinence. Accordingly, in another aspect of the present invention, pharmaceutically acceptable compositions are provided, wherein these compositions comprise any of the compounds as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents.

It will also be appreciated that certain of the compounds of present invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. According to the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, pharmaceutically acceptable salts, esters, salts of such esters, or any other adduct or derivative which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. A “pharmaceutically acceptable salt” means any non-toxic salt or salt of an ester of a compound of this invention that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of a voltage-gated sodium ion channel or calcium channel.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N⁺(C₁₋₄alkyl)₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil-soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of the present invention additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

Uses of Compounds and Pharmaceutically Acceptable Compositions

In yet another aspect, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain is provided comprising administering an effective amount of a compound, or a pharmaceutically acceptable composition comprising a compound to a subject in need thereof. In certain embodiments, a method for the treatment or lessening the severity of acute, chronic, neuropathic, or inflammatory pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof. In certain other embodiments, a method for the treatment or lessening the severity of radicular pain, sciatica, back pain, head pain, or neck pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a, subject in need thereof. In still other embodiments, a method for the treatment or lessening the severity of severe or intractable pain, acute pain, postsurgical pain, back pain, or cancer pain is provided comprising administering an effective amount of a compound or a pharmaceutically acceptable composition to a subject in need thereof.

In certain embodiments of the present invention an “effective amount” of the compound or pharmaceutically acceptable composition is that amount effective for treating or lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain.

The compounds and compositions, according to the method of the present invention, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of acute, chronic, neuropathic, or inflammatory pain, arthritis, migrane, cluster headaches, trigeminal neuralgia, herpetic neuralgia, general neuralgias, epilepsy or epilepsy conditions, neurodegenerative disorders, psychiatric disorders such as anxiety and depression, myotonia, arrythmia, movement disorders, neuroendocrine disorders, ataxia, multiple sclerosis, irritable bowel syndrome, incontinence, visceral pain, osteoarthritis pain, postherpetic neuralgia, diabetic neuropathy, radicular pain, sciatica, back pain, head or neck pain, severe or intractable pain, nociceptive pain, breakthrough pain, postsurgical pain, or cancer pain. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. The compounds of the invention are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular patient or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the medical arts. The term “patient”, as used herein, means an animal, preferably a mammal, and most preferably a human.

The pharmaceutically acceptable compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, the compounds of the invention may be administered orally or parenterally at dosage levels of about 0.01 mg/kg to about 50 mg/kg and preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

As described generally above, the compounds of the invention are useful as inhibitors of voltage-gated sodium ion channels or calcium channels, preferably N-type calcium channels. In one embodiment, the compounds and compositions of the invention are inhibitors of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2, and thus, without wishing to be bound by any particular theory, the compounds and compositions are particularly useful for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease, condition, or disorder. When activation or hyperactivity of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2, is implicated in a particular disease, condition, or disorder, the disease, condition, or disorder may also be referred to as a “NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8 or NaV1.9-mediated disease, condition or disorder” or a “CaV2.2-mediated condition or disorder”. Accordingly, in another aspect, the present invention provides a method for treating or lessening the severity of a disease, condition, or disorder where activation or hyperactivity of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 is implicated in the disease state.

The activity of a compound utilized in this invention as an inhibitor of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 may be assayed according to methods described generally in the Examples herein, or according to methods available to one of ordinary skill in the art.

In certain exemplary embodiments, compounds of the invention are useful as inhibitors of NaV1.8. In other embodiments, compounds of the invention are useful as inhibitors of NaV1.8 and CaV2.2. In still other embodiments, compounds of the invention are useful as inhibitors of CaV2.2. In yet other embodiments, compounds of the invention are useful as dual inhibitors of NaV1.8 and a TTX-sensitive ion channel such as NaV1.3 or NaV1.7.

It will also be appreciated that the compounds and pharmaceutically acceptable compositions of the present invention can be employed in combination therapies, that is, the compounds and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and/or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated”. For example, exemplary additional therapeutic agents include, but are not limited to: nonopioid analgesics (indoles such as Etodolac, Indomethacin, Sulindac, Tolmetin; naphthylalkanones such sa Nabumetone; oxicams such as Piroxicam; para-aminophenol derivatives, such as Acetaminophen; propionic acids such as Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Naproxen, Naproxen sodium, Oxaprozin; salicylates such as Asprin, Choline magnesium trisalicylate, Diflunisal; fenamates such as meclofenamic acid, Mefenamic acid; and pyrazoles such as Phenylbutazone); or opioid (narcotic) agonists (such as Codeine, Fentanyl, Hydromorphone, Levorphanol, Meperidine, Methadone, Morphine, Oxycodone, Oxymorphone, Propoxyphene, Buprenorphine, Butorphanol, Dezocine, Nalbuphine, and Pentazocine). Additionally, nondrug analgesic approaches may be utilized in conjunction with administration of one or more compounds of the invention. For example, anesthesiologic (intraspinal infusion, neural blocade), neurosurgical (neurolysis of CNS pathways), neurostimulatory (transcutaneous electrical nerve stimulation, dorsal column stimulation), physiatric (physical therapy, orthotic devices, diathermy), or psychologic (cognitive methods-hypnosis, biofeedback, or behavioral methods) approaches may also be utilized. Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Seventeenth Edition, Ed. Mark H. Beers and Robert Berkow, Merck Research Laboratories, 1999, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

The amount of additional therapeutic agent present in the compositions of this invention will be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably the amount of additional therapeutic agent in the presently disclosed compositions will range from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

The compounds of this invention or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the present invention, in another aspect, includes a composition for coating an implantable device comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the present invention includes an implantable device coated with a composition comprising a compound of the present invention as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. Suitable coatings and the general preparation of coated implantable devices are described in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccarides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition.

Another aspect of the invention relates to inhibiting one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample or a patient, which method comprises administering to the patient, or contacting said biological sample with a compound of formula I or, a composition comprising said compound. The term “biological sample”, as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of one or more of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, NaV1.9, or CaV2.2 activity in a biological sample is useful for a variety of purposes that are known to one of skill in the art. Examples of such purposes include, but are not limited to, the study of sodium ion channels in biological and pathological phenomena; and the comparative evaluation of new sodium ion channel inhibitors.

In order that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

EXAMPLES Synthesis of Exemplary Compounds of the Invention Example 1

In a 2 L three-necked round-bottomed flask equipped with an overhead stirrer and reflux condenser, anthranilamide 1 (20.0 g, 147 mmol) and potassium carbonate (28.4 g, 206 mmol) was suspended in 1 L dry ether and heated to reflux. o-Anisoyl chloride (32.5 g, 191 mmol) was added slowly to the refluxing mixture. After 3 hours at reflux, the reaction mixture was allowed to cool to room temperature, the ether was removed under reduced pressure, and the resulting residue was filtered and washed with water. The resulting solid was then suspended in 600 mL of 5% aq. NaOH solution and boiled for one hour. The reaction was allowed to cool to room temperature, then neutralized with acetic acid, upon which quinazilinone 2 was precipitated. Product 2 was collected by filtration, washed with water, and dried overnight in vacuo to yield 27 g (73%) of pure 2.

LC/MS (10-99%) M/Z 253.0 retention time 3.22 min; ¹H NMR (DMSO) δ3.86 (s, 3H), δ7.09 (t, 1H), δ 7.18 (d, 1H), δ 7.53 (m, 2H), δ 7.70 (m, 2H), δ 7.80 (m, 1H), δ 8.14 (d, 1H), δ 12.11 (s, 1H); ¹³C NMR (DMSO) δ 55.75, δ 111.86, δ 120.89, δ 120.97, δ 122.74, δ 125.75, δ 126.45, δ 127.26, δ 130.41, δ 132.13, δ 134.32, δ 148.97, δ 152.48, δ 157.12, δ 161.35

Quinazolinone 2 (20.0 g, 79.3 mmol) was suspended in 500 mL dry benzene in a 1 L round-bottomed flask equipped with a reflux condenser. N,N-Dimethylanaline (14.4 g, 119 mmol) was added and the reaction was refluxed for 30 minutes under nitrogen. Upon cooling to room temperature, phosphorus oxychloride (12.2 g, 79.3 mmol) was added and the reaction mixture was then refluxed for an additional 3 hours under nitrogen. The mixture was cooled to room temperature, poured over ice, and neutralized with saturated aqueous sodium bicarbonate. The solution was then extracted four times with toluene and the combined organic layers dried over magnesium sulfate, filtered, and concentrated in vacuo to a reddish-brown solid. The resulting 4-chloroquinazoline 3 was purified via flash chromatography (40% hexanes, 60% dichloromethane) to afford 20 g (93%) 3 as a yellow solid.

LC/MS (40-99%) M/Z 271.4 retention time 2.49 min; ¹HNMR (CDCl₃) δ3.89 (s, 3H), δ57.06 (d, 1H), δ 7.09 (d, 1H), δ 7.45 (m, 1H), δ 7.71 (m, 1H), δ 7.80 (m, 1H), δ 7.95 (m, 1H), δ 8.17 (d, 1H), δ 8.30 (d, 1H); ¹³C NMR (CDCl₃) δ 56.3 (d), δ 112.15 (d), δ 121.0 (s), δ 122.29 (s), δ 125.97 (s), δ 126.76 (s), δ 127.25 (d), δ 128.71 (d), δ 132.10 (m), δ 135.26 (s), δ 151.16 (s), δ 158.19 (s), δ 161.02 (s), δ 162.58 (s).

A 500 mL two-necked round-bottomed flask equipped with an addition funnel was charged with 4-Chloroquinazoline 3 (5.00 g, 18.5 mmol) and 80 mL dry dichloromethane under nitrogen. The mixture was cooled to ˜78° C. and 92 mL of 1M boron tribromide in dichloromethane was added dropwise via the addition funnel. The cooling bath was removed and the reaction allowed to stir for three hours at room temperature. The mixture was then cooled to 0° C. and slowly neutralized with saturated aqueous sodium bicarbonate, extracted 3 times with dichloromethane, and the combined organic solutions dried over magnesium sulfate, filtered, and concentrated in vacuo to a yellow solid. The residue was promptly dissolved in 30 mL of 2:1 dry THF/CH₂Cl₂, then treated with 2 M dimethlyamine in THF (46.3 mL, 92.5 mmol). After 30 min the solvent was removed under reduced pressure, the residue partitioned between dichloromethane and water, and the aqueous solution extracted 4 times with dichloromethane. The combined organic solutions were dried over magnesium sulfate, filtered, and concentrated in vacuo to an orange solid. Recrystallization from ethanol gave 2.61 g (53%) yellow crystalline 4.

LC/MS (10-99%) M/Z 266.0 retention time 2.59 min; ¹H NMR (DMSO) δ3.32 (s,), δ3.45 (s, 61-1), δ 6.93 (m, 2H), δ 7.35 (m, 1H), δ 7.46 (m, 1H), δ 7.78 (m, 2H), δ 8.21 (d, 1H), δ 8.43 (d, 1H); ¹³C NMR (DMSO) δ 41.62, 113.77, 117.18, 118.25, 118.97, 124.75, 126.15, 126.51, 128.96, 132.36, 133.11, 149.09, 159.22, 160.74, 161.69.

HCl salt:

A 250 mL round-bottomed flask was charged with quinazoline 4 (1.0 g, 3.8 mmol), 100 mL dry ether, 11 mL dry methanol, then sealed with a septum and placed in a sonicator with the bath temperature at 43° C. Upon complete dissolution of 4, 2 M ethereal HCl solution was added (1.9 mL, 3.8 mmol), causing immediate precipitation of 5. The solvent was removed in vacuo, and the salt twice re-suspended in dry ether, concentrated, and dried in vacuo. After drying overnight under vacuum, 1.13 g (98%) 5 was obtained as a pale yellow solid.

M/Z 266.0 retention time 2.59 min; ¹H NMR (DMSO) δ3.59 (s, 6H), δ 7.02 (m, 1H), δ 7.19 (d, 1H), S 7.49 (m, 1H), S 7.64 (m, 1H), δ 7.96 (m, 1H), δ 8.05 (d, 1H), δ 8.20 (d, 1H), δ 8.35 (d, 1H); ¹³C NMR (DMSO) δ 42.37, 112.07, 117.19, 119.23, 121.09, 126.15, 127.48, 130.45, 134.01, 134.67, 155.37, 158.61, 160.97.

Example 2 Synthesis of 2-(2-Methoxy-phenyl)-7-trifluoromethyl-3H-quinazolin-4-one

2-(2-Methoxy-benzoylamino)-4-trifluoromethyl-benzoic acid 2-Amino-4-trifluoro-benzoic acid (3.84 g, 18.73 mmol) was dissolved in 30 ml dry 1,4-Dioxane followed by the slow addition of O-Anisoyl chloride (3.3 ml, 24.35 mmol), then triethylamine (7.85 ml, 56.19 mmol) and stirred under a nitrogen atmosphere at room temperature for 2 hours. Solvent was remove under reduced pressure and organic was partitioned between water and EtOAc and the pH was adjusted to 3 with HCl. Organic layer was separated, dried over MgSO4, filtered and concentrated to an off white solid. Recovered 6.35 g 100% yield. LC/MS (10-99%) M/Z 339.9, retention time 3.58 minutes.

2-(2-Methoxy-benzoylamino)-4-trifluoromethyl-benzamide 2-(2-Methoxy-benzoylamino)-4-trifluoromethyl-benzoic acid (7.04 g, 20.77 mmol) was suspended in 0.5M solution of ammonia in 1,4-Dioxane (125 ml, 62.31 mmol), followed by the addition of triethylamine (5.78 ml, 41.54 mmol) then BOP reagent (12 g, 27.0 mmol) and stirred at room temperature for 16 hours. The product was collected by vacuum filtration and washed with water. The desired product was dried on the lyophilizer for 24 h. Recovered 3.8 g as a white solid. LC/MS (10-99%) M/Z 339.1, retention time 2.93 minutes.

2-(2-Methoxy-phenyl)-7-trifluoromethyl-3H-quinazolin-4-one 2-(2-Methoxy-benzoylamino)-4-trifluoromethyl-benzamide (3.8 g, 11.24 mmol) was suspended in 145 ml 5% aqueous NaOH solution then refluxed fro three hours at 120° C. The reaction was cooled to room temperature and adjusted to pH 4 causing the desired product to precipitate from solution. Solid was collected by vacuum filtration as a white solid and dried on the lyophilizer for 24 h. White solid 2.7 g, 75% yield. LC/MS (10-99%) M/Z 321.1, retention time 3.25 minutes.

Synthesis of 2-(2-Methoxy-phenyl)-7-methyl-3H-quinazolin-4-one

N-(2-Cyano-5-methyl-phenyl)-2-methoxy-benzamide 2-Amino-4-methyl anthronitrile (50.0 g, 378.3 mmol) was dissolved in 1 L dry pyridine and cooled to 0° C. O-Anisoyl chloride (63.0 ml, 453.96 mmol) was added dropwise over a 40 minute period and the reaction was allowed to warm to room temperature and stirred under a nitrogen atmosphere for 16 hours. The reaction was poured over 2 L of ice and the product formed a precipitate. The product was collected by vacuum filtration and dried for 3 days to produce the desired product a fluffy tan solid. Recovered 92.0 g 91% yield. LC/MS (10-99%) M/Z 267.2, retention time 3.34 minutes.

2-(2-Methoxy-phenyl)-7-methyl-3H-quinazolin-4-one N-(2-Cyano-5-methyl-phenyl)-2-methoxy-benzamide (47.0 g, 176.5 mmol) was suspended in 1 L of ethanol followed by the addition of a 6M aqueous NaOH solution (326 ml), then a 30% solution of H₂O₂ (100 ml). The reaction was refluxed for 3 hours, cooled to room temperature and poured over an equal volume of ice. The solution was adjusted to pH3.5 and the product precipitated from solution. Desired product was collected by vacuum filtration and dried on the lyophilizer for 24 h. 22.4 g, 48% yield. LC/MS (10-99%) M/Z 267.0, retention time 2.54 minutes.

5-Fluoro-4-methyl-anthranilic acid

2-Amino-5-fluoro-4-methyl-benzoic acid. Chloral hydrate (76 g) was dissolved in 1 L water and subsequently 1 kg Na₂SO₄, 94.1 g H₂NOH.HCl, and 51.3 g 4-fluoro-3-methyl aniline in 250 ml 5% aq. HCl were added. The suspension was heated to boiling and kept boiling for 1 minute. After cooling down to room temperature, the solid was filtered off and washed twice with warm water (40° C.). Yield after drying overnight at 60° C. under vacuum was 275 g, which was used without further purification or drying. The 275 g of crude product was slowly poured in 500 ml of concentrated H₂SO₄ at 50° C., such that the temperature was kept below 75° C. After completion of addition, the dark/purple solution was heated to 85° C. for 15 minutes. After cooling down to room temperature, the solution was poured in 2 L of ice water and was left standing for an half hour. The red solid was filtered and washed twice with cold water. Subsequently, the solid was dried under vacuum at 70° C. Yield: 69.9 g (quantitatively from 4-fluoro-3-methyl aniline) of a mixture of two regio isomers: 5-fluoro and 3-fluoro 3-methyl-isatin in a ratio of about 55:45. The mixture of isatins (69.4 g) was dissolved in 1 L 1N aq. NaOH and subsequently 100 ml of 30% aq. H₂O₂ was added drop wise, keeping the temperature below 30° C. After completion of addition, the mixture was heated to 45° C. until evolution of gas ceased. The solution was cooled to room temperature, filtered and acidified with glacial acetic acid. The precipitate formed was filtered off, washed twice with water and air-dried 45° C. Yield: 29.4 g of 5-fluoro-4-methyl-anthranilic acid iii.

2-Amino-5-trifluoromethyl-benzoic acid. 4-(trifluoromethyl)aniline (25 g, 0.15 mol) was dissolved in THF (275 mL), then treated with Boc anhydride (41 g, 0.19 mol), ET₃N (19 g, 0.19 mol), and 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was refluxed for 3 hours, the solvents removed in vacuo, and the organic residue dissolved in EtOAc, washed with 1 M NaOH, then 1 M HCl, then dried and concentrated. The resulting product was recrystallized from heptane yielding 39 g final product as a white solid. The solid (0.15 mol) was dissolved in THF (350 mL) and cooled to −78° C. under nitrogen, then treated dropwise with BuLi (1.6 M in hexane, 282 mL, 0.45 mol). After 1 h, the solution was warmed to 0° C. and held for 1.5 h. The mixture was poured onto excess solid CO₂ and stirred overnight at RT. After partitioning against 1 M HCl, the THF layer was evaporated and the residue dissolved in EtOAc, washed with 1 M HCl, then dried and concentrated. The solid product was triturated with hexan to yield the final product as a white solid (15.8 g). LC/MS retention time 2.70 min, m/z (obs, M−H)=304.1. Finally the Boc anthranilate (11.3 g) was dissolved in CH2CL2 (26 mL) and treated with TFA (21 mL). After stirring at RT for 2 h, the solution was dried in vacuo, the resulting residue dissolved in toluene (100 mL), concentrated to dryness, and the dissolution/drying process repeated twice more, yielding the desired product as a white solid (10.8 g), LC/MS retention time 1.2 min, m/z (obs, M−H)=204.0.

2-Amino-5-bromo-benzamide. The isatoic anhydride (15 g, 0.062 mol) was combined with 1 M aq. NH₄OH (340 mL) and stirred for 2 d at RT. The solid product was collected by filtration and dried in vacuo (6.6 g). LC/MS retention time 2.47 min, m/z obs=215.2.

To a stirring suspension of benzoyleneurea 1 (10.0 g, 61.7 mmol) and phosphorus oxychloride (20 ml) in a 500 mL three-necked round-bottomed flask equipped with a magnetic stirrer and reflux condenser, was added N,N-dimethylaniline (7.80 ml, 61.7 mmol) in a single portion. The suspension was heated at reflux for 3 hours and slowly formed a light red solution. The solution was concentrated under reduced pressure and the residue was poured onto ice (100 g). The solution was basified to pH=9.0 using concentrated aqueous sodium bicarbonate solution. The mixture was partitioned between CH₂Cl₂ and H₂O. The organic portion was dried (MgSO₄) and evaporated to dryness under reduced pressure. The residue was dissolved in anhydrous THF (75 ml) and cooled to 0° C. Dimethylaniline (67.7 mL, 135 mmol, 2.0 M in THF) was added dropwise, with stirring, over a period of 30 minutes. The solution was then stirred at 0° C. for 1 hour. The solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography using (70% hexanes, 30% ethyl acetate) to obtain 2 (7.90 g, 38.1 mmol, 62% yield) as a white solid.

¹H NMR (CDCl₃) δ3.43 (s, 6H), 7.40 (t, 1H), 7.69 (t, 1H), 7.78 (d, 1H), 8.02 (d, 1H); M+1 (obs)=208.0; R_(t)=2.26.

A 5 mL microwave reaction vessel was charged with a mixture of 2 (100 mg, 0.48 mmol), 2-methoxyphenylboronic acid (96 mg, 0.63 mmol), tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.048 mmol), sodium carbonate (1.20 mL, 0.48 mmol, 0.40 M aqueous solution), and acetonitrile (1.20 mL). The vessel was sealed and heated, with stirring, at 170° C. for 10 minutes via microwave irradiation. The organic portion was concentrated under reduced pressure and the residue was purified by silica gel chromatography using (80% hexanes, 20% ethyl acetate) to obtain 3 (120 mg, 0.43 mmol, 89% yield) as a white solid.

¹H NMR (CDCl₃) δ3.32 (s, 6H), 3.81 (s, 3H), 6.89-7.02 (m, 2H), 7.28-7.34 (m, 2H), 7.62 (t, 1H), 7.75 (d, 1H), 7.89 (d, 1H), 7.95 (d, 1H); M+1 (obs)=280.2; R_(t)=2.46.

2-Chloro-4-dimethylaminoquinazoline-7-carboxylic acid methyl ester. A stirring suspension of 2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-7-carboxylic acid methyl ester (12.2 g, 55.4 mmol), N,N-dimethylaniline (14.0 mL, 110.8 mmol), and POCl₃ (25 mL), under N₂, was heated at 100° C. for 15 minutes. The solution was evaporated to dryness under reduced pressure and the residual oil was poured into ice-water (800 mL). The mixture was made strongly basic by the addition of 50% aqueous NaOH solution at 0° C. The mixture was partitioned between CH₂Cl₂ and H₂O and the organic portion was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography using 70% hexanes/30% EtOAc to obtain the intermediate chloride as a white solid (5.1 g, 19.8 mmol). The obtained intermediate was dissolved in CH₂Cl₂ (100 mL). The solution was cooled to 0° C. followed by the addition of Et₃N (5.5 mL, 39.6 mmol) and dimethylamine hydrochloride (1.6 g, 19.8 mmol). The mixture was then stirred at 0° C. for 30 minutes. The mixture was evaporated to dryness and the obtained residue was purified via silica gel chromatography using 70% hexanes/30% EtOAc to obtain the desired amine as a white solid (3.3 g, 12.4 mmol, 11% yield). LC/MS (10-99%) M/Z 268.0 retention time 2.85 min.

6-Fluoro-N4,N4-dimethylquinazoline-2,4-diamine. A stirring mixture of (2-chloro-6-fluoro-quinazolin-4-yl)-dimethylamine (50 mg, 0.22 mmol), lithium bis(trimethylsilyl)amide (260 μL, 0.26 mmol, 1.0 M in hexanes), Pd₂(dba)₃ (20 mg, 0.022 mmol), 2-(dicyclohexyl)phosphinobiphenyl (19 mg, 0.053 mmol), and THF (1.0 mL) was heated in a sealed tube via microwave irradiation at 65° C. for 1.5 hours. 1.0 N aqueous HCl solution (3.0 mL) was added and the mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between H₂O and EtOAc. The organic portion was evaporated to dryness under reduced pressure. The obtained residue was purified via silica gel chromatography using 95% CH₂Cl₂/5% MeOH to obtain the desired amine as a tan solid (40 mg, 19.4 mmol, 88% yield). LC/MS (10-99%) M/Z 206.9 retention time 1.18 min.

1-(4-Dimethylamino-6-fluoroquinazolin-2-yl)-pyrrolidine-2,5-dione. A stirring mixture of 6-fluoro-N4,N4-dimethylquinazoline-2,4-diamine (30.0 mg, 0.13 mmol), succinic anhydride (12 mg, 0.12 mmol), and p-dioxane (500 μL) was heated in a sealed tube via microwave irradiation at 170° C. for 20 minutes. The mixture was purified via HPLC to obtain the desired succinate as a TFA salt (40 mg, 0.10 mmol, 76% yield). LC/MS (10-99%) M/Z 289.3 retention time 2.01 min.

1-(6-Fluoro-4-pyrrolidin-1-yl-quinazolin-2-yl)-pyrrolidin-2-one. A stirring mixture of 6-fluoro-4-pyrrolidin-1-yl-quinazolin-2-ylamine (30.0 mg, 0.14 mmol), 4-chlorobutyryl chloride (17 μL, 0.15 mmol), Et₃N (42 μL, 0.30 mmol), and p-dioxane (500 μL) was heated in a sealed tube via microwave irradiation at 170° C. for 20 minutes. The mixture was purified via HPLC to obtain the desired lactam as a TFA salt (45 mg, 0.11 mmol, 81% yield). LC/MS (10-99%) M/Z 301.2 retention time 2.24 min.

1-(4-Dimethylamino-6-fluoro-quinazolin-2-yl)-1H-pyrrole-3-carbaldehyde. A stirring mixture of 6-fluoro-N4,N4-dimethylquinazoline-2,4-diamine (20.0 mg, 0.10 mmol), 2,5-dimethyoxy-3-tetrahydrofurancarboxaldehyde (43 μL, 0.30 mmol), and AcOH (500 μL) was heated at 90° C. for 30 minutes. The mixture was evaporated to dryness and the obtained residue was purified via silica gel chromatography using 70% hexanes/30% EtOAc to obtain the desired aldehyde as a white solid (15 mg, 0.05 mmol, 50% yield). LC/MS (10-99%) M/Z 285.1 retention time 3.23 min.

(6-Methoxy-2-pyrrol-1-yl-quinazolin-4-yl)-dimethyl-amine. To a stirring solution pyrrole (310 mg, 4.6 mmol) and DMF (5.0 mL), under N₂, was added NaH (170 mg, 4.2 mmol, 60% in mineral oil). The mixture was stirred at room temperature for 10 minutes. To this solution was added (2-chloro-6-methoxyquinazolin-4-yl)dimethylamine (1.0 g, 4.2 mmol). The mixture was heated in a sealed tube via microwave irradiation at 220° C. for 20 minutes. The mixture was evaporated to dryness and the obtained residue was purified via silica gel chromatography using 70% hexanes/30% EtOAc to obtain the desired aldehyde as a white solid (15 mg, 0.05 mmol, 50% yield). LC/MS (10-99%) M/Z 269.0 retention time 2.39 min.

[2-(2-Chloro-pyrrol-1-yl)-6-methoxyquinazolin-4-yl]dimethyl-amine. To a stirring solution of (6-methoxy-2-pyrrol-1-yl-quinazolin-4-yl)dimethyl-amine (25 mg, 0.09 mmol) and THF (2.0 mL), under N₂, was added N-chlorosuccinimide (13 mg, 0.09 mmol). The solution was stirred at room temperature for 17 hours. The mixture was purified via HPLC to obtain the desired chloropyrrole as a TFA salt (23 mg, 0.06 mmol, 62% yield). LC/MS (10-99%) M/Z 303.0 retention time 2.71 min.

2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol. To a stirring solution of 2-(4-Chloro-7-methylquinazolin-2-yl)-phenol (100 mg, 0.35 mmol), Et₃N (72 μL, 0.52 mmol), and CH₂Cl₂ (300 μL) under N₂, was added 4-aminopiperidine (54 μL, 0.52 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness under reduced pressure. The residue was purified by silica gel chromatography using 98% CH₂Cl₂/2% MeOH to obtain the desired amine as a white solid (11 mg, 0.31 mmol, 89% yield). LC/MS (10-99%) M/Z 349.3 retention time 2.22 min.

Ethanesulfonic acid {1-[2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl}-amide. To a stirring solution of 2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol (30 mg, 0.09 mmol), Et₃N (25 μL, 0.18 mmol), and CH₂Cl₂ (500 μL) under N₂, was added ethanesulfonyl chloride (10 μL, 0.09 mmol). The mixture was stirred at room temperature for 3 hours. The mixture was purified via HPLC to obtain the desired sulfonamide as a TFA salt (33 mg, 0.06 mmol, 68% yield). LC/MS (10-99%) M/Z 427.3 retention time 2.80 min.

3-{1-[2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl}-1,1-dimethylsulfonylurea. To a stirring solution of 2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol (35 mg, 0.11 mmol), Et₃N (30 μL, 0.22 mmol), and CH₂Cl₂ (300 μL) under N₂, was added dimethylsulfamoyl chloride (12 μL, 0.11 mmol). The mixture was stirred at room temperature for 17 hours. The mixture was purified via HPLC to obtain the desired sulfonylurea as a TFA salt (44 mg, 0.08 mmol, 71% yield). LC/MS (10-99%) M/Z 442.4 retention time 2.84 min.

{1-[2-(2-Hydroxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl}-carbamic acid isobutyl ester. To a stirring solution of 2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol (30 mg, 0.09 mmol), Et₃N (25 μL, 0.18 mmol), and CH₂Cl₂ (300 μL) under N₂, was added isobutylchloroformate (12 μL, 0.09 mmol). The mixture was stirred at room temperature for 1 hour. The mixture was purified via HPLC to obtain the desired carbamate as a TFA salt (27 mg, 0.05 mmol. 58% yield). LC/MS (10-99%) M/Z 435.2 retention time 3.21 min.

Isobutylcarbamic acid 1-[2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl ester. To a stirring solution of 1-[2-(2-Methoxyphenyl)-7-methylquinazolin-4-yl]-piperidin-4-ol (100 mg, 0.30 mmol) and THF (500 μL) under N₂, was added phosgene (317 μL, 0.60 mmol, 20% in toluene). The mixture was stirred at room temperature for 15 minutes. Isobutylamine (300 μL, 3.0 mmol) was added dropwise over a 2 minute period followed by stirring at room temperature for 1 hour. The mixture was evaporated to dryness and the obtained residue was purified via silica gel chromatography using 97% CH₂Cl₂/3% MeOH to obtain the desired carbamate intermediate as a clear oil (90 mg, 0.20 mmol). To a stirring solution of the carbamate intermediate (90 mg, 0.20 mmol) and CH₂Cl₂ (15 mL), under N₂, at −78° C., was added BBr₃ (0.60 mL, 0.60 mmol, 1.0 M in CH₂Cl₂) dropwise over a period of 2 minutes. The mixture was then allowed to warm to room temperature and was then heated at 50° C. for 15 minutes. The mixture was poured into a saturated aqueous NaHCO₃ solution (80 mL) and the organic portion was evaporated to dryness. The residue was purified via HPLC to obtain the desired carbamate as a TFA salt (66 mg, 0.12 mmol, 39% yield). LC/MS (10-99%) M/Z 435.3 retention time 3.08 min.

N-{1-[2-(2-Hydroxy-phenyl)-7-methylquinazolin-4-yl]-piperidin-4-yl}-3-methylbutyramide. To a stirring solution of 2-[4-(4-Aminopiperidin-1-yl)-7-methylquinazolin-2-yl]-phenol (35 mg, 0.11 mmol), Et₃N (30 μL, 0.22 mmol), and CH₂Cl₂ (300 μL) under N₂, was added isovaleryl chloride (14 μL, 0.11 mmol). The mixture was stirred at room temperature for 17 hours. The mixture was purified via HPLC to obtain the desired sulfonamide as a TFA salt (37 mg, 0.07 mmol, 59% yield). LC/MS (10-99%) M/Z 419.3 retention time 2.77 min.

Synthesis of 2-(4-Ethoxy-quinazolin-2-yl)-phenol

2-(4-Ethoxy-quinazolin-2-yl)-phenol. 2-(4-Chloro-quinazolin-2-yl)-phenol (50 mg, 0.196 mmol) was placed in a microwave tube charged with a stir bar and dissolved 0.5 ml dry dichloromethane, followed by the addition of 2 ml dry ethanol. Tube was sealed with a cap and heated at 160 to 200° C. for one hour in CEM microwave. Solvent was removed under reduced pressure, reconstituted organic in DMSO and purified by Gilson HPLC. The desired compound was concentrated to a white solid as the TFA salt. LC/MS (10-99%) M/Z 267.2, retention time 2.57 minutes.

Synthesis 2-(4-Dimethylamino-quinazolin-2-yl)-6-methyl-phenol

[2-(2-Methoxy-3-methyl-phenyl)-quinazolin-4-yl]-dimethyl-amine To a stirring solution of [2-(2-Methoxy-phenyl)-quinazolin-4-yl]-dimethyl-amine (200 mg, 0.72 mmol) in dry THF under an argon atmosphere at −78° C. was added dropwise a 1.6M solution of nBuLi in hexanes (0.671 ml, 1.074 mmol). After 10 minutes MeI (0.076 ml, 1.22 mmol) was added and the reaction was allowed to warm to room temperature. After 10 minutes at room temperature the reaction was quenched with a saturated aqueous solution of NH₄Cl and partitioned between aqueous and EtOAc. Organic phase was separated, dried over MgSO₄, filtered and concentrated to a yellow oil. Purified by flash chromatograpy 10% EtOAc/90% hexanes to afford product as a white solid. Recovered 146 mg 50% yield. LC/MS (10-99%) M/Z 294.0, retention time 3.23 minutes.

2-(4-Dimethylamino-quinazolin-2-yl)-6-methyl-phenol To a stirring solution of [2-(2-Methoxy-phenyl)-quinazolin-4-yl]-dimethyl-amine (54 mg, 0.184 mmol) in CH₂Cl₂ at −78° C. under a nitrogen atmosphere was added BBr₃ (0.92 ml, 0.92 mmol). The reaction was allowed to warm to room temperature and the heated at 45° C. for 4 hours. The reaction was allowed to cool to room temperature and then quenched with an aqueous solution of NaHCO₃ until pH8. Organic layer was separated, dried over MgSO₄, filtered, and concentrated to a yellow solid. Purified by Gilson HPLC and desired product was isolated as the TFA salt. LC/MS (10-99%) M/Z 280.2, retention time 2.55 minutes.

Synthesis of 2-(4-Dimethylamino-quinazolin-2-yl)-4-morpholin-4-yl-phenol

[2-(2-Methoxy-5-morpholin-4-yl-phenyl)-quinazolin-4-yl]-dimethyl-amine To a tube charged with a stirbar was added Pd₂(dba)₃ (51.1 mg, 0.0558 mmol), biphenyl-2-yl-di-tert-butyl-phosphane (67 mg, 0.223 mmol), NaOtBu (80 mg, 0.837 mmol) in 2 ml dry toluene was added 4-Bromo-2-(4-dimethylamino-quinazolin-2-yl)-phenol (200 mg, 0.558 mmol) and morpholine (0.073 ml, 0.837 mmol). The reaction was sealed with a screw cap and heated at 100° C. in an oil bath for 16 h. Purified by flash chromatograpy 30%-60% EtOAc/hexanes to afford product as a white solid. Recovered 100 mg 49% yield. LC/MS (10-99%) M/Z 365.0, retention time 2.07 minutes.

2-(4-Dimethylamino-quinazolin-2-yl)-4-morpholin-4-yl-phenol To a stirring solution of [2-(2-Methoxy-5-morpholin-4-yl-phenyl)-quinazolin-4-yl]-dimethyl-amine (109 mg, 0.299 mmol) in CH₂Cl₂ at −78° C. under a nitrogen atmosphere was added BBr₃ (1.5 ml, 1.5 mmol). The reaction was allowed to warm to room temperature and was heated at 40° C. for 2 hours. The reaction was quenched with an aqueous solution of NaHCO₃ until pH 8. Organic layer was separated, dried over MgSO₄, filtered, and concentrated to a yellow solid. Purified by Gilson HPLC and desired product was isolated as the TFA salt. LC/MS (10-99%) M/Z 351.4, retention time 1.89 minutes.

Synthesis of 2-(4-Dimethylamino-quinazolin-2-yl)-4-methyl-phenol

[2-(2-Methoxy-5-methyl-phenyl)-quinazolin-4-yl]-dimethyl-amine To a stirring solution of [[2-(5-Bromo-2-methoxy-phenyl)-quinazolin-4-yl]-dimethyl-amine (200 mg, 0.558 mmol) in dry THF under an argon atmosphere at −78° C. was added dropwise a 1.6M solution of nBuLi in hexanes (0.76 ml, 1.23 mmol). After 10 minutes MeI (0.054 ml, 1.23 mmol) was added and the reaction was allowed to warm to room temperature. After 10 minutes at room temperature the reaction was quenched with a saturated aqueous solution of NH₄Cl and partitioned between aqueous and EtOAc. Organic phase was separated, dried over MgSO₄, filtered and concentrated to a yellow oil. Purified by flash chromatograpy 30% EtOAc/70% hexanes to afford product as a white solid. Recovered 146 mg 89% yield. LC/MS (10-99%) M/Z 294.4, retention time 2.64 minutes.

2-(4-Dimethylamino-quinazolin-2-yl)-4-methyl-phenol To a stirring solution of [2-(2-Methoxy-5-methyl-phenyl)-quinazolin-4-yl]-dimethyl-amine (146 mg, 0.498 mmol) in CH₂Cl₂ at −78° C. under a nitrogen atmosphere was added BBr₃ (2.49 ml, 2.49 mmol). The reaction was allowed to warm to room temperature and was complete after 2 hours. The reaction was quenched with an aqueous solution of NaHCO₃ until pH8. Organic layer was separated, dried over MgSO₄, filtered, and concentrated to a yellow solid. Purified by Gilson HPLC and desired product was isolated as the TFA salt. LC/MS (10-99%) M/Z 280.2, retention time 2.65 minutes.

Synthesis of 2-(2′-methylsulfonylphenyl)-4-dimethylaminoquinazoline

2-(2′-methylsulfonylphenyl)-4-dimethylaminoquinazoline. A 2 mL Personal Chemistry Microwave reaction vessel with a stir bar was charged with 2-(2′-bromophenyl)-4-dimethylaminoquinazoline (0.020 g, 61 mmol), copper (I) iodide (0.017 g, 91 mmol), sodium methanesulfinate (0.010 g, 97 mmol), and 0.5 mL of DMF.¹ This mixture was irradiated at 180° C. for 10 min. After cooling, water and ether were added, and an extraction was performed. The ether layer was then filtered through celite and then extracted once again, using approximately 20% NH₄OH to remove additional copper. After concentrating, the product was redissolved in a 50/50 solution of DMSO/MeOH. Purification was conducted on LC/MS to provide the TFA salt. LC/MS (10-99%) M/Z 328.3, retention time 3.03 min.

Synthesis of 2-(2′-anilino)-4-dimethylaminoquinazoline

2-(2′-anilino)-4-dimethylaminoquinazoline. Zinc powder (1.18 g, 18.0 mmol) was added to a solution of 2-(2′-nitrophenyl)-4-dimethylaminoquinazoline (0.530 g, 1.80 mmol) in acetic acid (10.9 mL, 190 mmol) at 0° C. The reaction mixture solidified, but then began to stir again after the ice bath was removed.^(3,4) The reaction mixture was stirred for three hours at room temperature. Deionized water (approximately 10 mL) was then added, and a solution formed, followed by formation of a precipitate. This solution was then taken slightly basic with NaHCO₃(aq). The product was extracted three times with ethyl acetate, dried with MgSO₄, filtered, and concentrated. Approximately 20 mg of the product was redissolved in a 50/50 solution of DMSO/MeOH and purified by LC/MS to provide the bis-TFA salt. LC/MS (10-99%) M/Z 265.0, retention time 2.81 min.

Synthesis of 2-(2′-ethylsulfanylphenyl)-4-dimethylaminoquinazoline

2-(2′-ethylsulfanylphenyl)-4-dimethylaminoquinazoline. Potassium carbonate (0.052 g, 0.374 mmol) and ethanethiol (0.055 mL, 0.748 mmol) were added to a solution of 2-(2′-fluorophenyl)-4-dimethylaminoquinazoline (0.020 g, 0.0748 mmol) in N,N-dimethylformamide (1 mL) in a microwave reaction vessel with a stir bar. This mixture was irradiated in the microwave at 135° C. for 1.5 hours. The resulting mixture was filtered and then purified by LC/MS to provide the TFA salt. LC/MS (10-99%) M/Z 310.2, retention time 3.27 min.

Synthesis of 2-(2′-cyanophenyl)-4-dimethylaminoquinazoline

2-(2′-cyanophenyl)-4-dimethylaminoquinazoline. A round bottom flask was charged with 2-(2′-bromophenyl)-4-dimethylaminoquinazoline (0.010 g, 0.0305 mmol), potassium cyanide (0.0040 g, 0.0609 mmol), tetrakis(triphenylphosphine)palladium(0) (0.0018 g, 0.00152 mmol), copper(I)iodide (0.00058 g, 0.00305 mmol), and acetonitrile (0.50 mL) and heated to reflux overnight.⁵ After cooling to room temperature, ethyl acetate was added and filtered through celite. An extraction was then performed, using ammonium hydroxide (approximately 20%) to remove additional copper. After being concentrated, the product was redissolved in a 50/50 solution of DMSO/MeOH and purified by LC/MS to provide the TFA salt. LC/MS (10-99%) M/Z 275.2, retention time 2.85 min.

Synthesis of 2-(2′-isopropenylphenyl)-4-dimethylaminoquinazoline

2-(2′-isopropenylphenyl)-4-dimethylaminoquinazoline. A 0.5 M solution of isopropenyl magnesium bromide (0.898 mL, 0.449 mmol) was added to a solution of 2-(2′-fluorophenyl)-4-dimethylaminoquinazoline (0.040 g, 0.150 mmol) in ethylene glycol dimethyl ether (1 mL) in a microwave vessel with a stir bar. The sample was irradiated in the microwave for 5 min at 170° C. Deionized water (approximately 2 mL) was then added. An extraction was then performed with ether. After being concentrated, the product was redissolved in a 50/50 solution of DMSO/MeOH and purified by LC/MS to provide the TFA salt. LC/MS (10-99%) M/Z 289.8, retention time 3.23 min.

Synthesis of 2-(2′-hydroxyphenyl)-4-dimethylamino-6-methoxyquinazoline

2-(2′-hydroxyphenyl)-4-dimethylamino-6-methoxyquinazoline. A microwave reaction vessel with a stir bar was charged with 2-(2′-acetoxyphenyl)-4-dimethylamino-6-bromoquinazoline (0.100 g, 0.259 mmol), copper(I) iodide (0.0245 g, 0.129 mmol), N,N-dimethylformamide (0.90 mL), and a 0.5 M solution of sodium methoxide (1.04 mL, 0.518 mmol) in methanol. The sample was irradiated in the microwave for 20 min at 150° C. After cooling, the sample was diluted with ether and then filtered through celite. Next, an extraction was performed, using ammonium hydroxide (approximately 20%) to remove additional copper. After being concentrated, the product was redissolved in a 50/50 solution of DMSO/MeOH and purified by LC/MS (20-99%) to provide the TFA salt. Approximate yield=60% (by LC/MS). LC/MS (10-99%) M/Z 296.4, retention time 2.31 min.

Synthesis of 4-Fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester

3-Bromo-4-fluoro-benzoic acid methyl ester. 3-Bromo-4-fluoro-benzoic acid (2.5 g, 11.42 mmol) was placed in a 100 ml round bottom flask charged with a stir bar, sealed with a septum and placed under a nitrogen atmosphere and dissolved in 9 ml dry THF and 3 ml dry MeOH. A 2.0M solution of TMSdiazomethane in ether (6.28 ml, 12.56 mmol) was added dropwise to the stirring solution of the acid. Conversion of the acid to the ester was complete after twenty minutes according to LC/MS analysis. The solvent was removed under reduced pressure and product was used without further purification. Recovered a light oil (2.66 g, 100% yield) LC/MS (10-99%) M/Z 234, retention time 3.09 minutes.

4-Fluoro-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzoic acid methyl ester. To a round bottom flask charged with a stir bar was added 3-Bromo-4-fluoro-benzoic acid methyl ester (1.66 g, 7.12 mmol), Bis(pinacolato)diboron (2.2 g, 8.5 mmol), potassium acetate (2.1 g, 21.3 mmol), and (0.35 g, 0.43 mmol) [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1). The reaction was sealed with a septum, evacuated and the placed under a nitrogen atmosphere, followed by the addition of 20 ml of dry DMSO. The reaction was heated at 80° C. in an oil bath for two hours. The reaction was allowed to cool to room temperature and partitioned between ethyl acetate and water. Organic layer was separated, and the aqueous layer was extracted two more times. All organics were combined, dried over MgSO₄, filtered and concentrated under reduced pressure to a black oil. The product was purified by flash chromatography using a gradient of EtOAc/Hexanes 0 to 60%, to afford the desired product as a white solid (1.48 g, 74% yield). LC/MS (10-99%) M/Z 281.4, retention time 2.73 minutes.

The quinazoline 1 (1.5 g, 3.0 mmol) was dissolved in THF (150 mL). After cooling to −78° C., t-BuLi (1.7 M in heptane, 1.76 mL) was added dropwise. After stirring for 10 min at −78° C., CO₂ (crushed) was added to the solution, then warmed up to RT and stirred for 30 min. Quenched the reaction with H₂O (100 mL), diluted with EtOAc (100 mL), The organic layer was dried, concentrated, purified by flash chromatography (1%-10% MeOH/DCM) to obtain 2 (600 mg, 43% yield).

Synthesis of 2-(2′-hydroxyphenyl)-4-dimethylamino-6-morpholinoquinazoline

2-(2′-hydroxyphenyl)-4-dimethylamino-6-morpholinoquinazoline. A dry reaction tube with a septa screw cap under N₂ was charged with tris(dibenzylideneacetone)dipalladium(0) (0.012 g, 13.0 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binapthyl (0.024 g, 38.8 mmol), cesium carbonate (0.097 g, 298 mmol), toluene (0.25 mL), 2-(2′-acetoxyphenyl)-4-dimethylamino-6-bromoquinazoline (0.050 g, 129 mmol), and morpholine (23 μL, 259 mmol), in that order.² This mixture was then heated to 80° C. for 24 hours. After cooling, the mixture was diluted with ether, filtered through celite and silica gel, and concentrated. The product was redissolved in a 50/50 solution of DMSO/MeOH and purified by LC/MS to provide the bis-TFA salt. LC/MS (10-99%) M/Z 351.0, retention time 2.75 min.

The quinazoline 1 (0.2 g, 0.62 mmol) was dissolved in CH₃CN (5 mL). After cooling to −10° C. (ice/NaCl), CCl₄, DIEA and DMAP were added. After stirring for 10 min, a solution of dibenzyl phosphite in CH₃CN (2 mL) was slowly added over 10 min. Stirring was continued at −10° C. for 2 h, then at RT for 24 h. Quenched by addition of 0.5 M K₂HPO₄, diluted with water (15 mL), extracted with DCM (30 mL), dried, concentrated, purified by flash chromatography (100% DCM) to obtain 2 (168 mg, 47% yield) as a colorless oil. LC/MS (10-99%) M/Z 586.0 retention time 2.54 min.

To a solution of the quinazoline 2 (0.168 g, 0.29 mmol) in DCM (1.5 mL) was added TMSBr (0.079 mL, 0.61 mmol) at 0° C. The reaction was stirred for 1 h at 0° C., then for 1 h at RT. The reaction was quenched with water (3 mL) and stirred for 15 min. The aqueous layer was washed with EtOAc (5 mL), and dried with lyophilizer overnight to give desired product 3 as white foam (0.14 g. 100% yield). LC/MS (10-99%) M/Z 406.0 retention time 3.32 min.

To a solution of the quinazoline 3 (0.14 g, 0.36 mmol) in MeOH (3 mL) was added NaOMe (1.44 mL, 0.72 mmol) at RT. The reaction was stirred overnight at RT. The reaction mixture was concentrated using rotavap (25° C.), then the residue was taken up with water (75 mL) and washed with EtOAc (3×50 mL). The aqueous phase was dried with lyophilizer to give final product 4 (0.14 g, 98% yield) as solid. LC/MS (10-99%) M/Z 406.0 retention time 3.32 min.

2-{7-Methyl-4-[methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amino]-quinazolin-2-yl}-phenol

[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine 4-Chloro-2-(2-methoxy-phenyl)-7-methyl-quinazoline (400 mg, 1.48 mmol) was dissolved in 10 ml dry DMF followed by the addition of C-(5-Methyl-[1,3,4]oxadiazol-2-yl)-methylamine oxalate (234 mg, 1.48 mmol) then triethylamine (413 μL, 2.96 mmol). After 6 hours the reaction was complete, partitioned between EtOAc and water. The organic phase was separated, dried over MgSO₄, filtered and concentrated to an oil. Purified by flash chromatography 60% EtOAc/40% hexanes to afford the desired product a white solid. Recovered 290 mg 56% yield. LC/MS (10-99%) M/Z 348.4, retention time 2.17 minutes.

[2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine To a stirring suspension of freshly washed sodium hydride (42 mg, 1.04 mmol) in dry DMF at 0° C. under a nitrogen atmosphere was added the [2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine (180 mg, 0.518 mmol, in 5 ml DMF). After 30 minutes at 0° C., MeI (74 μL, 1.19 mmol) was added and the reaction was allowed to warm to room temperature. After one hour the reaction was quenched with water and extracted 3 times with EtOAc. Organics were combined, dried over MgSO₄, filtered and concentrated to a yellow oil. Purified by flash chromatography 50/50 EtOAc/hexanes to afford the desired product as a clear oil. 128 mg, 66% yield. LC/MS (10-99%) M/Z 376.1, retention time 2.06 minutes.

2-{7-Methyl-4-[methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amino]-quinazolin-2-yl}-phenol To a stirring solution of [2-(2-Methoxy-phenyl)-7-methyl-quinazolin-4-yl]-methyl-(5-methyl-[1,3,4]oxadiazol-2-ylmethyl)-amine (128 mg, 0.341 mmol) in 7 ml dry CH₂Cl₂ at −78° C. under a nitrogen atmosphere was added BBr₃ (1.71 ml, 1.71 mmol) dropwise. The reaction was allowed to warm to room temperature and after three hours the reaction was quenched with a saturated aqueous solution of NaHCO₃ until pH8. The organic was separated, dried over MgSO₄, filtered and concentrated to a light yellow oil. Purified by Gilson HPLC and compound was isolated as the TFA salt. LC/MS (10-99%) M/Z 362.3, retention time 2.12 minutes.

To a solution of the quinazoline (187 mg, 0.63 mmol) in CH₂Cl₂ (5 mL) was added pyridine (0.11 mL, 1.36 mmol) at RT. After cooling to 0° C. a solution of acetyl chloride (50 μL, 0.70 mmol) in CH₂Cl₂ (5 mL) was added, stirring was continued for 45 Min at RT and the solvent was removed in vacuo. Chromatography over silica (hexanes/EtOAc/NEt₃: 2:1:0.05) afforded compound 1 as a white solid (90 mg, 42%). Compound 1: LC/MS (10-99%): m/z=338 [M+H]⁺, R_(t): 3.28 min.

Other compounds of general formula I have been prepared by methods substantially similar to those described above. The characterization data for these compounds is summarized in Table 3 below, and compound numbers correspond to the compounds depicted in Table 2.

TABLE 3 Exemplary Characterization Data for Compounds of Formula I Cmpd # LC_MASS_PLUS 15 308.40 16 306.00 164 320.00 194 389.20 195 404.20 198 302.00, 302.20, 302.00 202 328.20, 328.20, 328.00 241 268.30 250 346.00 252 310.00 253 344.00 254 319.00 255 333.00 256 348.00 257 319.00 258 289.80 259 249.80, 250.40 260 386.20 261 357.00 262 275.20 263 358.00 264 325.00 265 296.60, 296.40, 296.40 266 345.20 267 310.20, 310.00 268 351.00 269 310.00 270 340.10 271 298.10 272 314.00 273 328.20 274 284.00 275 300.10 276 328.10 277 286.90 278 306.00 279 280.20 280 380.00 281 334.00, 334.00 282 336.00 283 351.00 284 336.00, 336.00 285 322.00, 322.00, 322.00, 322.00 286 307.00 287 378.00 288 405.00 289 349.00 290 292.00 291 322.00 292 342.00 293 294.00 294 358.20 295 374.00 296 382.40 297 256.80 298 239.00 299 339.80 300 279.00 301 386.00 302 307.20 303 318.00 304 296.20 305 278.00 306 291.80 307 239.00 308 289.00 309 270.00 310 402.20 311 342.00 312 342.00 313 320.20 314 309.00 315 399.00 316 318.00 317 332.00 318 332.00 319 315.00 320 329.00 321 343.00 322 357.00 323 342.00 324 342.00 325 368.00, 368.10 326 352.00 327 369.80 328 456.20 329 381.80 330 384.00 331 395.80 332 322.00, 322.20 333 284.00 334 334.00 335 280.00 336 296.00 337 306.00 338 286.80 339 286.80 340 329.40 341 356.20 342 329.40 343 463.20 344 491.60 345 353.20 346 315.80 347 359.00 348 402.20 349 341.80 350 359.80 351 384.80 352 371.80 353 369.60 354 343.00 355 441.00 356 353.80 357 314.00 358 320.00 359 323.00 360 289.00 361 322.20 362 400.00 363 386.00 364 390.00 365 306.00 366 385.80 367 370.00 368 374.00 369 320.00 370 320.00 371 322.00 372 320.00 373 308.00, 308.00 374 340.00 375 356.00 376 280.20, 280.00 377 300.40, 300.00 378 282.00 379 326.20 380 351.20 381 338.20 382 336.20 383 309.20 384 407.40 385 334.20 386 323.40 387 380.20 388 294.00 389 350.00 390 345.00 391 326.00 392 352.80 393 323.00 394 286.00 395 344.00 396 340.00 397 326.00 398 314.00 399 312.00 400 343.20 401 354.00 402 340.00 403 282.00 404 285.00 405 283.20 406 292.00 407 464.00 408 298.00 409 273.00 410 326.20 411 326.20 412 356.00 413 359.20 414 355.00 415 338.00 416 370.00 417 328.00 418 298.20 419 279.80 420 281.80 421 340.90 422 269.30, 269.20 423 303.00 424 372.80 425 272.80 426 307.00 427 322.20 428 324.20 429 284.00, 285.00 430 286.00 431 429.00 432 439.00 433 443.00 434 456.00 435 486.00 436 326.20 437 328.00 438 253.00 439 257.00 440 299.20 441 273.00 442 414.40 443 286.00 444 302.20 445 330.00 446 328.20 447 355.40 448 412.00 449 286.00 450 338.20, 338.00 451 352.20 452 267.00 453 326.20 454 284.20 455 309.20 456 399.20 457 312.00 458 340.20 459 302.00 460 316.00 461 344.00 462 328.00 463 378.00 464 316.00 465 327.80 466 371.80, 371.60 467 355.60 468 356.80 469 359.00 470 435.20 471 368.00 472 344.00 473 282.20 474 281.20 475 355.00 476 302.20 477 316.20 478 344.20 479 328.20 480 378.00 481 316.20 482 282.00 483 286.00 484 328.00 485 324.20 486 353.80 487 377.80 488 365.00 489 339.80 490 267.00 491 281.00 492 310.20 493 352.20 494 342.00 495 328.00 496 402.20, 402.40 497 439.20 498 421.00 499 367.00 500 397.20 501 365.00 502 270.00 508 290.90 516 403.40 517 403.40 518 403.60 519 403.40 520 408.40 521 409.20 522 432.40 523 432.20 524 431.40 525 432.40 526 432.40 527 437.40 528 437.40 529 446.40 530 452.40 531 463.00 532 370.00 533 382.20 534 384.20 535 398.20 536 437.40 537 439.40 538 439.40 539 439.20 540 377.40 541 384.00 542 386.00 543 391.20 544 391.20 545 397.40 546 397.40 547 397.40 548 411.40 549 368.20 550 420.20 551 441.40 552 446.00 553 449.40 554 394.00 555 450.20 556 330.00 557 332.20 558 334.00 559 346.00 560 348.00 561 372.00 562 383.20 563 383.20 564 383.20 565 383.20 566 387.80 567 388.80 568 403.40 569 412.00 570 412.00 571 412.00 572 349.20 573 361.00 574 375.20 575 389.20 576 411.20 577 411.20 586 281.00 587 342.40 588 356.00 589 358.20 590 365.20, 365.20 591 369.20, 369.20 592 370.00 593 372.40 594 383.20, 383.20, 383.20, 383.20 595 384.00 596 391.20 597 397.40 598 337.80 599 350.00 600 352.00 601 376.00 602 387.20 603 391.80 604 393.00 605 416.00 606 416.20 607 416.00 608 353.00 609 415.20 610 415.20 611 416.20 612 421.00 613 430.20 614 431.20 615 436.20 616 447.00 617 459.20 618 493.00 619 353.80 620 353.80 621 365.80 622 367.80 623 367.80 624 367.80 625 383.00 626 409.40 627 421.00 628 423.20 629 423.20 630 423.20 631 429.20, 429.00 632 430.00 633 435.20 634 437.00 635 437.40 636 479.20 637 361.00 638 362.20 639 364.80 640 366.00 641 366.00 642 367.20 643 367.80 644 368.00 645 370.00 646 375.20 647 375.20 648 375.20 649 375.20 650 375.20 651 381.00 652 381.00 653 381.20 654 381.20 655 381.20 656 388.20 657 395.00 658 395.20 659 418.00 660 352.00 661 365.80 662 365.80 663 385.80 664 404.20 665 404.00 666 406.00 667 425.20 668 430.20 669 430.20 670 446.00 671 429.40 672 433.20 673 457.20 674 430.00 675 418.20 676 436.20 677 378.00 678 269.80 679 411.20 680 427.20 681 399.80 682 420.20 683 420.00 684 434.20 685 454.20 686 399.80 687 414.20 688 420.00 689 432.00 690 367.80, 367.80 691 323.00 692 324.00 693 326.00 694 326.00 695 326.00 696 338.00 697 340.00 698 342.00 699 342.00 700 349.00 701 353.20 702 353.00 703 353.00 704 353.20 705 353.20 706 354.00 707 354.00 708 356.00 709 355.80 710 355.80 711 367.00 712 367.20 713 367.20 714 367.20 715 368.00 716 367.80 717 371.80, 373.10 718 375.00 719 381.00 720 382.00 721 382.20 722 383.20 723 385.00 724 389.20 725 390.00 726 393.20 727 393.20 728 397.20 729 400.20 730 403.40 731 404.20 732 407.40 733 411.20 734 413.20 735 415.40 736 416.20 737 419.00 738 419.20 739 421.00 740 423.20 741 428.20 742 429.40 743 430.20 744 431.40 745 431.20 746 441.40 747 446.00 748 450.20 749 432.00 750 470.20 751 352.00 752 352.00 753 352.00 754 374.00 755 373.80 756 374.00 757 378.00 758 378.00 759 378.00 760 416.20 761 429.20 762 432.00 763 441.40 764 470.20 765 477.00 766 326.00 767 366.00 768 365.80 769 388.20 770 326.00 771 352.20 772 364.20 773 380.80 774 397.20 775 407.40 776 413.20 777 415.20 778 421.00 779 429.20 780 350.00 781 283.80 782 294.00 783 296.00 784 298.00 785 312.00 786 314.00 787 314.00 788 324.00 789 328.00 790 340.00 791 343.80 792 310.00 793 347.00 794 347.00 795 351.00 796 373.80 797 326.00 798 326.00 799 326.20 800 338.00 801 372.00 802 372.00 803 381.80 804 377.20 805 377.20 806 377.20 807 384.00 808 391.00 809 391.20 810 414.40 811 348.00 812 362.00 813 362.00 814 381.80 815 399.80 816 399.80 817 402.00 818 425.80 819 426.00 820 442.00 821 474.20 822 425.20 823 425.20 824 429.20 825 453.00 826 426.00 827 373.80 828 407.40 829 413.00 830 423.20 831 395.80 832 416.00 833 416.00 834 430.00 835 395.80 836 410.00 837 409.80 838 416.00 839 364.00, 364.00 840 439.20 841 319.00 842 319.80 843 321.80 844 321.80 845 322.00 846 334.00 847 336.20 848 337.80 849 337.80 850 344.80 851 349.20, 349.00 852 349.20 853 349.20 854 350.00 855 350.00 856 352.20 857 353.00 858 352.00 859 352.00 860 363.00 861 363.00 862 363.00 863 363.20 864 363.80, 364.00 865 364.00 866 363.80 867 370.80 868 373.20 869 377.00 870 378.00 871 379.20 872 385.20 873 385.80 874 385.80 875 389.20 876 389.20 877 392.80, 393.20, 393.30 878 396.20 879 398.20, 398.20 880 399.00 881 284.30 882 412.20 883 417.40 884 417.20 885 432.20 886 417.40 887 419.20 888 357.00 889 364.40 890 371.00 891 348.00, 348.20 892 360.20 893 386.20 894 393.20 895 409.00 896 417.40 897 425.00 898 346.00 899 412.40 900 426.20 901 427.40 902 443.20 903 455.20 904 489.20 905 350.20 906 350.20 907 362.00 908 364.00 909 364.00 910 364.00 911 378.60 912 405.60 913 419.40 914 419.20 915 425.00 916 431.40 917 433.40 918 433.40 919 475.20 920 358.20 921 361.00 922 362.00 923 362.00 924 363.20 925 364.00 926 366.00 927 371.20 928 371.40 929 371.20 930 377.20 931 377.20 932 368.00, 368.00 933 400.20 934 400.00 935 403.40 936 407.60 937 409.20 938 411.20 939 412.00 940 415.20 941 417.00 942 419.20 943 424.40 944 425.20 945 426.00 946 427.00 947 427.60 948 437.20 949 442.20 950 446.00 951 348.00 952 348.00 953 348.00 954 370.00 955 370.00 956 370.00 957 374.00 958 374.20 959 374.00 960 412.40 961 425.00, 425.00 962 430.00 963 437.60 964 440.00 965 466.40 966 473.00 967 364.20, 364.00 968 290.20 969 292.00 970 306.20 971 308.60 972 310.00 973 324.20 974 336.00 975 340.00 976 306.60 977 343.00 978 347.00 979 370.00 980 322.20 981 322.40, 322.00 982 356.00 983 368.40 984 368.00 985 378.20 986 405.60 987 409.40 988 416.20 989 420.00 990 423.40 991 427.40 992 429.20 993 431.40 994 435.40 995 439.20 996 445.20 997 447.00 998 466.40 999 432.40 1000 369.00 1001 381.00 1002 409.20 1003 431.60 1004 432.40 1005 509.40 1006 384.00 1007 384.00 1008 425.40 1009 445.20 1010 451.20 1011 452.40 1012 495.40 1013 381.00 1014 382.00 1015 411.20 1016 444.40 1017 457.40 1018 384.00 1019 352.40 1020 368.00 1021 391.20 1022 391.20 1023 328.40 1024 434.40 1025 382.00 1026 358.20 1027 369.20 1028 369.20 1029 383.20 1030 340.20 1031 409.40 1032 420.40 1033 368.00 1034 445.20 1035 330.40 1036 340.00 1037 356.00 1038 359.80 1039 363.20 1040 367.00 1041 390.00 1042 342.00 1043 342.60 1044 388.40 1045 343.80 1048 455.00 1049 338.00 1050 324.20 1051 433.60 1052 427.00 1053 443.20 1054 398.20 1055 435.20 1056 415.20 1057 417.40 1058 393.00 1059 361.00 1060 422.00 1065 385.20 1066 353.10 1067 354.10 1068 367.10 1069 380.90 1070 388.30 1071 353.10 1072 368.10 1073 410.00 1074 383.90 1075 429.10 1083 352.00, 351.90, 352.30, 352.20, 352.30, 352.30, 352.00 1084 350.00 1085 363.00 1086 377.00 1087 384.00, 384.00 1088 380.00 1089 362.00 1090 410.00 1091 426.00 1092 370.00 1101 293.00 1102 307.00 1103 334.00 1106 374.10, 374.00 1107 379.30 1108 421.10, 421.00, 421.00 1109 435.50 1110 407.50 1111 399.30 1112 413.30 1113 427.30 1114 391.30 1115 405.50 1116 377.30 1117 441.50, 441.00 1118 410.90 1119 335.90 1120 355.80, 355.90 1121 394.90 1122 407.50 1123 343.00, 341.90 1124 427.10 1125 396.00 1127 461.30 1128 393.80 1133 443.00 1134 419.80 1135 453.00 1136 378.00 1137 463.00, 463.00 1138 457.00 1141 504.00 1142 420.20 1143 422.20 1144 436.00 1145 448.20 1146 370.10 1147 457.50 1148 463.10, 463.10 1151 435.80 1152 450.00 1153 407.60 1155 518.10 1156 482.00 1157 485.50 1158 432.20 1159 473.10 1160 432.20 1161 468.50 1162 393.80 1163 444.00 1164 450.00 1165 511.00 1166 467.00 1167 363.30 1168 463.00 1169 482.00 1170 415.00 1171 467.00 1172 511.00 1173 491.00 1174 495.00 1175 365.90 1176 380.30 1179 321.80 1180 560.00 1181 337.20 1182 280.00 1183 259.20 1184 500.20, 500.20, 500.20 1185 353.00 1186 526.80 1190 350.20 1191 392.00 1192 376.00 1193 404.20 1194 462.20 1195 427.20 1196 407.40 1197 391.10

Methods:

(A) Micromass MUX LCT 4 channel LC/MS, Waters 60F pump, Gilson 215 4 probe autosampler, Gilson 849 injection module, 1.5 mL/min/column flow rate, 10-99% CH₃CN (0.035% TFA)/H₂O (0.05 TFA) gradient, Phenomenex Luna 5u C18 columns (50×4.60 mm), Waters MUX UV-2488 UV detector, Cedex 75 ELSD detectors.

(B) PESciex API-150-EX LC/MS, Shimadzu LC-8A pumps, Gilson 215 autosampler, Gilson 819 injection module, 3.0 mL/min flow rate, 10-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gradient, Phenomenex Luna 5u C18 column (50×4.60 mm), Shimadzu SPD-10A UVN is detector, Cedex 75 ELSD detector.

(C) PESciex API-150-EX LC/MS, Shimadzu LC-8A pumps, Gilson 215 autosampler, Gilson 819 injection module, 3.0 mL/min flow rate, 40-99% CH₃CN (0.035% TFA)/H₂O (0.05% TFA) gradient, Phenomenex Luna 5u C18 column (50×4.60 mm), Shimadzu SPD-10A UVN is detector, Cedex 75 ELSD detector.

Assays for Detecting and Measuring NaV Inhibition Properties of Compounds

A) Optical Methods for Assaying NaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gated sodium ion channels. Antagonist properties of test compounds were assessed as follows. Cells expressing the NaV of interest were placed into microtiter plates. After an incubation period, the cells were stained with fluorescent dyes sensitive to the transmembrane potential. The test compounds were added to the microtiter plate. The cells were stimulated with either a chemical or electrical means to evoke a NaV dependent membrane potential change from unblocked channels, which was detected and measured with trans-membrane potential-sensitive dyes. Antagonists were detected as a decreased membrane potential response to the stimulus. The optical membrane potential assay utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescence resonance energy transfer in single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays and instrumentation for screening ion-channel targets” Drug Discov Today 4(9): 431-439).

B) VIPR® Optical Membrane Potential Assay Method with Chemical Stimulation

Cell Handling and Dye Loading

24 hours before the assay on VIPR, CHO cells endogenously expressing a NaV1.2 type voltage-gated NaV are seeded in 96-well poly-lysine coated plates at 60,000 cells per well. Other subtypes are performed in an analogous mode in a cell line expressing the NaV of interest.

-   1) On the day of the assay, medium is aspirated and cells are washed     twice with 225 μL of Bath Solution #2 (BS#2). -   2) A 15 uM CC2-DMPE solution is prepared by mixing 5 mM coumarin     stock solution with 10% Pluronic 127 1:1 and then dissolving the mix     in the appropriate volume of BS#2. -   3) After bath solution is removed from the 96-well plates, the cells     are loaded with 80 μL of the CC2-DMPE solution. Plates are incubated     in the dark for 30 minutes at room temperature. -   4) While the cells are being stained with coumarin, a 15 μL oxonol     solution in BS#2 is prepared. In addition to DiSBAC₂(3), this     solution should contain 0.75 mM ABSC1 and 30 μL veratridine     (prepared from 10 mM EtOH stock, Sigma #V-5754). -   5) After 30 minutes, CC2-DMPE is removed and the cells are washed     twice with 225 μL of BS#2. As before, the residual volume should be     40 μL. -   6) Upon removing the bath, the cells are loaded with 80 μL of the     DiSBAC₂(3) solution, after which test compound, dissolved in DMSO,     is added to achieve the desired test concentration to each well from     the drug addition plate and mixed thoroughly. The volume in the well     should be roughly 121 μL. The cells are then incubated for 20-30     minutes. -   7) Once the incubation is complete, the cells are ready to be     assayed on VIPR® with a sodium addback protocol. 120 μL of Bath     solution #1 is added to stimulate the NaV dependent depolarization.     200 μL tetracaine was used as an antagonist positive control for     block of the NaV channel.

Analysis of VIPR® Data:

Data are analyzed and reported as normalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 nm channels. Background intensities are then subtracted from each assay channel. Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which there are no cells. The response as a function of time is then reported as the ratios obtained using the following formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final (R_(f)) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R=R_(f)/R_(i) is then calculated. For the Na⁺ addback analysis time windows, baseline is 2-7 sec and final response is sampled at 15-24 sec.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$ where R is the ratio response of the test compound Solutions [mM] Bath Solution #1: NaCl 160, KCl 4.5, CaCl₂ 2, MgCl₂ 1, HEPES 10, pH 7.4 with NaOH Bath Solution #2 TMA-Cl 160, CaCl₂ 0.1, MgCl₂ 1, HEPES 10, pH 7.4 with KOH (final K concentration ˜5 mM) CC2-DMPE: prepared as a 5 mM stock solution in DMSO and stored at −20° C. DiSBAC₂(3): prepared as a 12 mM stock in DMSO and stored at −20° C. ABSC1: prepared as a 200 mM stock in distilled H₂O and stored at room temperature

Cell Culture

CHO cells are grown in DMEM (Dulbecco's Modified Eagle Medium; GibcoBRL #10569-010) supplemented with 10% FBS (Fetal Bovine Serum, qualified; GibcoBRL #16140-071) and 1% Pen-Strep (Penicillin-Streptomycin; GibcoBRL #15140-122). Cells are grown in vented cap flasks, in 90% humidity and 10% CO₂, to 100% confluence. They are usually split by trypsinization 1:10 or 1:20, depending on scheduling needs, and grown for 2-3 days before the next split.

C) VIPR® Optical Membrane Potential Assay Method with Electrical Stimulation

The following is an example of how NaV1.3 inhibition activity is measured using the optical membrane potential method#2. Other subtypes are performed in an analogous mode in a cell line expressing the NaV of interest.

HEK293 cells stably expressing NaV1.3 are plated into 96-well microtiter plates. After an appropriate incubation period, the cells are stained with the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₂(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM ABSC1 in H₂O

Hank's Balanced Salt Solution (Hyclone #SH30268.02) supplemented with 10 mM HEPES (Gibco #15630-080)

Loading Protocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalent volume of 10% pluronic, followed by vortexing in required amount of HBSS containing 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE. 50 μL of 2×CC2-DMPE is to wells containing washed cells, resulting in a 10 μM final staining concentration. The cells are stained for 30 minutes in the dark at RT.

2×DISBAC₂(3) with ABSC1=6 μM DISBAC₂(3) and 1 mM ABSC1: The required amount of 10 mM DISBAC₂(3) is added to a 50 ml conical tube and mixed with 1 μL 10% pluronic for each mL of solution to be made and vortexed together. Then HBSS/HEPES is added to make up 2× solution. Finally, the ABSC1 is added.

The 2×DiSBAC₂(3) solution can be used to solvate compound plates. Note that compound plates are made at 2× drug concentration. Wash stained plate again, leaving residual volume of 50 μL. Add 50 uL/well of the 2×DiSBAC₂(3) w/ ABSC1. Stain for 30 minutes in the dark at RT.

The electrical stimulation instrument and methods of use are described in ION Channel Assay Methods PCT/US01/21652, herein incorporated by reference. The instrument comprises a microtiter plate handler, an optical system for exciting the coumarin dye while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current- or voltage-controlled amplifier, and a device for inserting electrodes in, well. Under integrated computer control, this instrument passes user-programmed electrical stimulus protocols to cells within the wells of the microtiter plate.

Reagents

Assay buffer #1

140 mM NaCl, 4.5 mM KCl, 2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 10 mM glucose, pH 7.40, 330 mOsm

Pluronic stock (1000×): 100 mg/mL pluronic 127 in dry DMSO

Oxonol stock (3333×): 10 mM DiSBAC₂(3) in dry DMSO

Coumarin stock (1000×): 10 mM CC2-DMPE in dry DMSO

ABSC1 stock (400×): 200 mM ABSC1 in water

Assay Protocol

-   -   1. Insert or use electrodes into each well to be assayed.     -   2. Use the current-controlled amplifier to deliver stimulation         wave pulses for 3 s. Two seconds of pre-stimulus recording are         performed to obtain the un-stimulated intensities. Five seconds         of post-stimulation recording are performed to examine the         relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 nm channels. Background intensities are then subtracted from each assay channel. Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which there are no cells. The response as a function of time is then reported as the ratios obtained using the following formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final (R_(f)) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R=R_(f)/R_(i) is then calculated.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as tetracaine, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$ where R is the ratio response of the test compound.

Electrophysiology Assays for NaV Activity and Inhibition of Test Compounds

Patch clamp electrophysiology was used to assess the efficacy and selectivity of sodium channel blockers in dorsal root ganglion neurons. Rat neurons were isolated from the dorsal root ganglions and maintained in culture for 2 to 10 days in the presence of NGF (50 ng/ml) (culture media consisted of NeurobasalA supplemented with B27, glutamine and antibiotics). Small diameter neurons (nociceptors, 8-12 μm in diameter) have been visually identified and probed with fine tip glass electrodes connected to an amplifier (Axon Instruments). The “voltage clamp” mode has been used to assess the compound's IC50 holding the cells at −60 mV. In addition, the “current clamp” mode has been employed to test the efficacy of the compounds in blocking action potential generation in response to current injections. The results of these experiments have contributed to the definition of the efficacy profile of the compounds.

Voltage-Clamp Assay in DRG Neurons

TTX-resistant sodium currents were recorded from DRG somata using the whole-cell variation of the patch clamp technique. Recordings were made at room temperature (˜22° C.) with thick walled borosilicate glass electrodes (WPI; resistance 3-4 MΩ)) using an Axopatch 200B amplifier (Axon Instruments). After establishing the whole-cell configuration, approximately 15 minutes were allowed for the pipette solution to equilibrate within the cell before beginning recording. Currents were lowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Series resistance was compensated 60-70% and was monitored continuously throughout the experiment. The liquid junction potential (−7 mV) between the intracellular pipette solution and the external recording solution was not accounted for in the data analysis. Test solutions were applied to the cells with a gravity driven fast perfusion system (SF-77; Warner Instruments).

Dose-response relationships were determined in voltage clamp mode by repeatedly depolarizing the cell from the experiment specific holding potential to a test potential of +10 mV once every 60 seconds. Blocking effects were allowed to plateau before proceeding to the next test concentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA (1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), CaCl₂ (1.26), KCl (5.33), KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3), glucose (5.6), HEPES (10), CdCl2 (0.4), NiCl2 (0.1), TTX (0.25×10⁻³).

Current-Clamp Assay for NaV Channel Inhibition Activity of Compounds

Cells were current-clamped in whole-cell configuration with a Multiplamp 700A amplifier (Axon Inst). Borosilicate pipettes (4-5 MOhm) were filled with (in mM):150 K-gluconate, 10 NaCl, 0.1 EGTA, 10 Hepes, 2 MgCl₂, (buffered to pH 7.34 with KOH). Cells were bathed in (in mM): 140 NaCl, 3 KCl, 1 MgCl, 1 CaCl, and 10 Hepes). Pipette potential was zeroed before seal formation; liquid junction potentials were not corrected during acquisition. Recordings were made at room temperature.

Following these procedures, representative compounds of the present invention were found to possess desired voltage gated sodium channel activity and selectivity.

Assays for Detecting and Measuring CaV Inhibition Properties of Compounds

A) Optical Methods for Assaying CaV Inhibition Properties of Compounds:

Compounds of the invention are useful as antagonists of voltage-gated calcium ion channels. Antagonist properties of test compounds were assessed as follows. Cells expressing the CaV of interest were placed into microtiter plates. After an incubation period, the cells were stained with fluorescent dyes sensitive to the transmembrane potential. The test compounds were added to the microtiter plate. The cells were stimulated with electrical means to evoke a CaV dependent membrane potential change from unblocked channels, which was detected and measured with trans-membrane potential-sensitive dyes. Antagonists were detected as a decreased membrane potential response to the stimulus. The optical membrane potential assay Utilized voltage-sensitive FRET sensors described by Gonzalez and Tsien (See Gonzalez, J. E. and R. Y. Tsien (1995) “Voltage sensing by fluorescence resonance energy transfer in single cells” Biophys J 69(4): 1272-80, and Gonzalez, J. E. and R. Y. Tsien (1997) “Improved indicators of cell membrane potential that use fluorescence resonance energy transfer” Chem Biol 4(4): 269-77) in combination with instrumentation for measuring fluorescence changes such as the Voltage/Ion Probe Reader (VIPR®) (See, Gonzalez, J. E., K. Oades, et al. (1999) “Cell-based assays and instrumentation for screening ion-channel targets” Drug Discov Today 4(9): 431-439).

VIPR® optical membrane potential assay method with electrical stimulation

The following is an example of how CaV2.2 inhibition activity is measured using the optical membrane potential method. Other subtypes are performed in an analogous mode in a cell line expressing the CaV of interest.

HEK293 cells stably expressing CaV2.2 are plated into 96-well microtiter plates. After an appropriate incubation period, the cells are stained with the voltage sensitive dyes CC2-DMPE/DiSBAC2(3) as follows.

Reagents:

100 mg/mL Pluronic F-127 (Sigma #P2443), in dry DMSO

10 mM DiSBAC₆(3) (Aurora #00-100-010) in dry DMSO

10 mM CC2-DMPE (Aurora #00-100-008) in dry DMSO

200 mM Acid Yellow 17 (Aurora #VABSC) in H₂O

370 mM Barium Chloride (Sigma Cat# B6394) in H₂O

Bath X

160 mM NaCl (Sigma Cat# S-9888)

4.5 mM KCl (Sigma Cat# P-5405)

1 mM MgCl2 (Fluka Cat#63064)

10 mM HEPES (Sigma Cat# H-4034)

pH 7.4 using NaOH

Loading Rotocol:

2×CC2-DMPE=20 μM CC2-DMPE: 10 mM CC2-DMPE is vortexed with an equivalent volume of 10% pluronic, followed by vortexing in required amount of HBSS containing 10 mM HEPES. Each cell plate will require 5 mL of 2×CC2-DMPE. 50 μL of 2×CC2-DMPE is added to wells containing washed cells, resulting in a 10 μM final staining concentration. The cells are stained for 30 minutes in the dark at RT.

2×CC2DMPE & DISBAC₆(3)=8 μM CC2DMPE & 2.5 μM DISBAC₆(3): Vortex together both dyes with an equivalent volume of 10% pluronic (in DMSO). Vortex in required amount of Bath X with beta-cyclodextrin. Each 96well cell plate will require 5 ml of 2XCC2DMPE. Wash plate with ELx405 with Bath X, leaving a residual volume of 50 μL/well. Add 50 μL of 2XCC2DMPE & DISBAC₆(3) to each well. Stain for 30 minutes in the dark at RT.

1.5×AY17=750 μM AY17 with 15 mM BaCl₂: Add Acid Yellow 17 to vessel containing Bath X. Mix well. Allow solution to sit for 10 minutes. Slowly mix in 370 mM BaCl₂. This solution can be used to solvate compound plates. Note that compound plates are made at 1.5× drug concentration and not the usual 2×. Wash CC2 stained plate, again, leaving residual volume of 50 μL. Add 100 uL/well of the AY17 solution. Stain for 15 minutes in the dark at RT. Run plate on the optical reader.

The electrical stimulation instrument and methods of use are described in ION Channel Assay Methods PCT/US01/21652, herein incorporated by reference. The instrument comprises a microtiter plate handler, an optical system for exciting the coumarin dye while simultaneously recording the coumarin and oxonol emissions, a waveform generator, a current- or voltage-controlled amplifier, and a device for inserting electrodes in well. Under integrated computer control, this instrument passes user-programmed electrical stimulus protocols to cells within the wells of the microtiter plate.

Assay Protocol

Insert or use electrodes into each well to be assayed.

Use the current-controlled amplifier to deliver stimulation wave pulses for 3-5 s. Two seconds of pre-stimulus recording are performed to obtain the un-stimulated intensities. Five seconds of post-stimulation recording are performed to examine the relaxation to the resting state.

Data Analysis

Data are analyzed and reported as normalized ratios of background-subtracted emission intensities measured in the 460 nm and 580 nm channels. Background intensities are then subtracted from each assay channel. Background intensities are obtained by measuring the emission intensities during the same time periods from identically treated assay wells in which there are no cells. The response as a function of time is then reported as the ratios obtained using the following formula:

${R(t)} = \frac{\left( {{intensity}_{460\mspace{14mu}{nm}} - {background}_{460\mspace{14mu}{nm}}} \right)}{\left( {{intensity}_{580\mspace{14mu}{nm}} - {background}_{580\mspace{14mu}{nm}}} \right)}$

The data is further reduced by calculating the initial (R_(i)) and final (R_(f)) ratios. These are the average ratio values during part or all of the pre-stimulation period, and during sample points during the stimulation period. The response to the stimulus R=R_(f)/R_(i) is then calculated.

Control responses are obtained by performing assays in the presence of a compound with the desired properties (positive control), such as mibefradil, and in the absence of pharmacological agents (negative control). Responses to the negative (N) and positive (P) controls are calculated as above. The compound antagonist activity A is defined as:

$A = {\frac{R - P}{N - P}*100.}$ where R is the ratio response of the test compound.

Electrophysiology Assays for CaV Activity and Inhibition of Test Compounds

Patch clamp electrophysiology was used to assess the efficacy of calcium channel blockers expressed in HEK293 cells. HEK293 cells expressing CaV2.2 have been visually identified and probed with fine tip glass electrodes connected to an amplifier (Axon Instruments). The “voltage clamp” mode has been used to assess the compound's IC50 holding the cells at −100 mV. The results of these experiments have contributed to the definition of the efficacy profile of the compounds.

Voltage-Clamp assay in HEK293 cells expressing CaV2.2

CaV2.2 calcium currents were recorded from HEK293 cells using the whole-cell variation of the patch clamp technique. Recordings were made at room temperature (−22° C.) with thick walled borosilicate glass electrodes (WPI; resistance 3-4 MΩ) using an Axopatch 200B amplifier (Axon Instruments). After establishing the whole-cell configuration, approximately 15 minutes were allowed for the pipette solution to equilibrate within the cell before beginning recording. Currents were lowpass filtered between 2-5 kHz and digitally sampled at 10 kHz. Series resistance was compensated 60-70% and was monitored continuously throughout the experiment. The liquid junction potential (−7 mV) between the intracellular pipette solution and the external recording solution was not accounted for in the data analysis. Test solutions were applied to the cells with a gravity driven fast perfusion system (SF-77; Warner Instruments).

Dose-response relationships were determined in voltage clamp mode by repeatedly depolarizing the cell from the experiment specific holding potential to a test potential of +20 mV for 50 ms at frequencies of 0.1, 1, 5, 10, 15, and 20 Hz. Blocking effects were allowed to plateau before proceeding to the next test concentration.

Solutions

Intracellular solution (in mM): Cs—F (130), NaCl (10), MgCl₂ (1), EGTA (1.5), CaCl₂ (0.1), HEPES (10), glucose (2), pH=7.42, 290 mOsm.

Extracellular solution (in mM): NaCl (138), BaCl₂ (10), KCl (5.33), KH₂PO₄ (0.44), MgCl₂ (0.5), MgSO₄ (0.41), NaHCO₃ (4), Na₂HPO₄ (0.3), glucose (5.6), HEPES (10).

Following these procedures, representative compounds of the present invention were found to possess desired N-type calcium channel modulation activity and selectivity. 

1. A method of treating or lessening the severity of a disease, disorder, or condition selected from arthritis, migraine, cluster headaches, epilepsy or epilepsy conditions, osteoarthritis pain, head pain or neck pain, comprising the step of administering to said patient an effective amount of a compound of formula IA-ii:

or a pharmaceutically acceptable salt thereof, wherein: a) the ring formed by R¹ and R² taken together is selected from:

and the ring formed by R¹ and R² taken together, are each optionally and independently substituted at one or more substitutable carbon or nitrogen atoms with z independent occurrences of —R⁴, wherein z is 0-5; b) wherein z is 0-5, and R⁴ groups, when present, are each independently halogen, CN, NO₂, —N(R′)₂, —CH₂N(R′)₂, —OR′, —CH₂OR′, —SR′, —CH₂SR′, —COOR′, —NRCOR′, —CON(R′)₂, —OCON(R′)₂, COR′, —NHCOOR′, —SO₂R′, —SO₂N(R′)₂, or an optionally substituted group selected from C₁-C₆aliphatic, aryl, heteroaryl, cycloaliphatic, heterocycloaliphatic, arylC₁-C₆alkyl, heteroarylC₁-C₆alkyl, cycloaliphaticC₁-C₆alkyl, or heterocycloaliphaticC₁-C₆alkyl; c) wherein x is 1, and R³ is an optionally substituted group selected from C₁-C₆aliphatic d) wherein y is 0; and e) R^(5a) is —OH; and f) each occurrence of R′ is independently hydrogen or an optionally substituted C₁₋₆ aliphatic group, a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.
 2. The method of claim 1, wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of voltage-gated sodium channels.
 3. The method of claim 1, wherein the disease, condition, or disorder is implicated in the activation or hyperactivity of calcium channels.
 4. The method of claim 1, wherein the disease, condition, or disorder is head pain or neck pain.
 5. The method of claim 1, wherein R³ is at the 6-position of the quinazoline ring.
 6. The method of claim 1, wherein R³ is at the 7-position of the quinazoline ring.
 7. The method of claim 1, comprising administering a compound selected from: Cmpd Compound #

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8. The method of claim 1, wherein R³ is substituted at the 6-position of the quinazoline ring, y is 0, and compounds have formula III:


9. The method of claim 1, wherein R³ is substituted at the 7-position of the quinazoline ring, y is 0, and compounds have formula IV: 